ChemWiki - User contributions [en]

It:sitagliptin page

2006-12-08T16:04:04Z

Rih05: /* 3D Structures of Sitagliptin */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

==Structure of Sitgliptin==
===3D Structures of Sitagliptin===
<div align="center">
In order to see the 3D structure in anaglyph 3D mode, special Red/Blue anaglyph glassess will be needed.
[[Image:RedBlue3DGlasses.JPG]]
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ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
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ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
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ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
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ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
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ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
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==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

*The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====Dosage Forms and Strengths====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.<br>Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.<br>Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
*Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

*Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]
* [http://www.glucagon.com/JanuviaProductInsertOctober2006.pdf Januvia Product Insert]
* [http://www.medicalnewstoday.com/medicalnews.php?newsid=25962 Medical News today]
* [http://www.glucagon.com/JANUVIAUSPPatientinformationOct-06.pdf Patient Information Sheet]

File:RedBlue3DGlasses.JPG

2006-12-08T16:02:49Z

Rih05: picture of 3d glassess

picture of 3d glassess

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2006-12-08T15:48:40Z

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2006-12-08T15:43:46Z

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Template:Chem-Data

2006-12-08T15:43:00Z

Rih05:

<noinclude>

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| {{{CASNo}}}
|-
! {{chembox header}} | Properties
|-
| [http://en.wikipedia.org/wiki/Density Density] & [http://en.wikipedia.org/wiki/Phase_%28matter%29 phase]
| {{{Density}}} g/cm³ 
|-
| [http://en.wikipedia.org/wiki/Solubility Solubility in water]
| {{{Sol_Water}}} g/100 ml (25°C) 
|-



| [http://en.wikipedia.org/wiki/Melting_point Melting point]
| {{{Mp}}} K 
|-
| [http://en.wikipedia.org/wiki/Boiling_point Boiling point]
| {{{Bp}}} K
|-
| [http://en.wikipedia.org/wiki/Acid_dissociation_constant Acidity] (p''K''<sub>a</sub>) 
| {{{pKa}}}
|-
| [http://en.wikipedia.org/wiki/Acid_dissociation_constant Basicity] (p''K''<sub>b</sub>) 
| {{{pKb}}}
|-
| [http://en.wikipedia.org/wiki/Specific_rotation Chiral rotation <nowiki>[α]</nowiki><sub>D</sub>] 
| {{{Rotation}}}°
|-
| [[Viscosity]]
| {{{Viscosity}}} [[Poise|cP]] at 25°C 
|-
! {{chembox header}} | Structure
|-
| [[Orbital_hybridisation#Molecule_shape|Molecular shape]] 
| {{{Mol_Shape}}} 
|-
| [[Coordination geometry|Coordination<br />geometry]] 
| {{{Coordination}}} 
|-
| [[Crystal structure]] 
| {{{Crystal_Structure}}} 
|-
| [[Dipole#Molecular_dipoles|Dipole moment]]
| {{{DM}}} [[Debye|D]]
|-
! {{chembox header}} | Hazards 
|-
| [[Material safety data sheet|MSDS]]
| [[{{PAGENAME}} (data page)#Material Safety Data Sheet|External MSDS]] 
|-
| Main [[Worker safety and health|hazard]]s
| {{{Hazards}}} 
|-
| [[NFPA 704]]
| {{{NFPA}}}
|-
| [[Flash point]]
| {{{Fp}}}°C
|-
| [[Risk and Safety Statements|R/S statement]]
| [[List of R-phrases|R]]: {{{R-S}}} <br /> [[List of S-phrases|S]]: ?
|-
| [[RTECS]] number
| {{{RTECS}}}
|-
! {{chembox header}} | [[{{PAGENAME}} (data page)|Supplementary data page]]
|-
| [[{{PAGENAME}} (data page)#Structure and properties|Structure and<br />properties]]
| [http://en.wikipedia.org/wiki/Refractive_index ''n''], [http://en.wikipedia.org/wiki/Dielectric_constant ε<sub>r</sub>], etc.
|-
| [[{{PAGENAME}} (data page)#Thermodynamic properties|Thermodynamic<br />data]]
| Phase behaviour<br />Solid, liquid, gas
|-
| [[{{PAGENAME}} (data page)#Spectral data|Spectral data]]
| [[UV/VIS spectroscopy|UV]], [[Infrared spectroscopy|IR]], [[nuclear magnetic resonance spectroscopy|NMR]], [[Mass spectrometry|MS]]
|-
! {{chembox header}} | Related compounds
|-
| Other [[Ion|anion]]s 
| {{{Other_anion}}} 
|-
| Other [[Ion|cation]]s 
| {{{Ohter_cation}}} 
|-
| Related compounds

| {{{Relative_Compounds}}}
|-
| {{chembox header}} | <small>Except where noted otherwise, data are given for<br /> materials in their [[standard state|standard state (at 25 °C, 100 kPa)]]<br />[[wikipedia:Chemical infobox|Infobox disclaimer and references]]</small>
|-
|}
{{Chem-Data_Structure}}

Template:Chem-Data

2006-12-08T15:41:27Z

Rih05:

<noinclude>

</noinclude>{| class="toccolours" border="1" style="float: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse; width: 280px"
! {{chembox header}} | {{PAGENAME}} 
|-
| align="center" colspan="2" bgcolor="#ffffff" | [[Image:{{PAGENAME}}.jpg|200px|{{PAGENAME}}]] 
|-
! {{chembox header}} | General
|-
| [http://en.wikipedia.org/wiki/IUPAC Systematic name]
| {{{IUPACName}}}

|-
| Other names
| {{{OtherNames}}}
|-
| [http://en.wikipedia.org/wiki/Chemical_formula Molecular formula]
| {{{Formula}}}
|-
| [http://en.wikipedia.org/wiki/Chemical_file_format SMILES] 
| {{{SMILES}}}
|-
| [http://en.wikipedia.org/wiki/Molar_mass Molar mass]
| {{{MolarMass}}}
|-
| Appearance
| {{{Appearance}}}
|-
| [http://en.wikipedia.org/wiki/CAS_registry_number CAS number]
| {{{CASNo}}}
|-
! {{chembox header}} | Properties
|-
| [http://en.wikipedia.org/wiki/Density Density] & [http://en.wikipedia.org/wiki/Phase_%28matter%29 phase]
| {{{Density}}} g/cm³ 
|-
| [http://en.wikipedia.org/wiki/Solubility Solubility in water]
| {{{Sol_Water}}} g/100 ml (25°C) 
|-



| [http://en.wikipedia.org/wiki/Melting_point Melting point]
| {{{Mp}}} K 
|-
| [http://en.wikipedia.org/wiki/Boiling_point Boiling point]
| {{{Bp}}} K
|-
| [http://en.wikipedia.org/wiki/Acid_dissociation_constant Acidity] (p''K''<sub>a</sub>) 
| {{{pKa}}}
|-
| [Basicity] (p''K''<sub>b</sub>) 
| {{{pKb}}}
|-
| [[Specific rotation|Chiral rotation <nowiki>[α]</nowiki><sub>D</sub>]] 
| {{{Rotation}}}°
|-
| [[Viscosity]]
| {{{Viscosity}}} [[Poise|cP]] at 25°C 
|-
! {{chembox header}} | Structure
|-
| [[Orbital_hybridisation#Molecule_shape|Molecular shape]] 
| {{{Mol_Shape}}} 
|-
| [[Coordination geometry|Coordination<br />geometry]] 
| {{{Coordination}}} 
|-
| [[Crystal structure]] 
| {{{Crystal_Structure}}} 
|-
| [[Dipole#Molecular_dipoles|Dipole moment]]
| {{{DM}}} [[Debye|D]]
|-
! {{chembox header}} | Hazards 
|-
| [[Material safety data sheet|MSDS]]
| [[{{PAGENAME}} (data page)#Material Safety Data Sheet|External MSDS]] 
|-
| Main [[Worker safety and health|hazard]]s
| {{{Hazards}}} 
|-
| [[NFPA 704]]
| {{{NFPA}}}
|-
| [[Flash point]]
| {{{Fp}}}°C
|-
| [[Risk and Safety Statements|R/S statement]]
| [[List of R-phrases|R]]: {{{R-S}}} <br /> [[List of S-phrases|S]]: ?
|-
| [[RTECS]] number
| {{{RTECS}}}
|-
! {{chembox header}} | [[{{PAGENAME}} (data page)|Supplementary data page]]
|-
| [[{{PAGENAME}} (data page)#Structure and properties|Structure and<br />properties]]
| [http://en.wikipedia.org/wiki/Refractive_index ''n''], [http://en.wikipedia.org/wiki/Dielectric_constant ε<sub>r</sub>], etc.
|-
| [[{{PAGENAME}} (data page)#Thermodynamic properties|Thermodynamic<br />data]]
| Phase behaviour<br />Solid, liquid, gas
|-
| [[{{PAGENAME}} (data page)#Spectral data|Spectral data]]
| [[UV/VIS spectroscopy|UV]], [[Infrared spectroscopy|IR]], [[nuclear magnetic resonance spectroscopy|NMR]], [[Mass spectrometry|MS]]
|-
! {{chembox header}} | Related compounds
|-
| Other [[Ion|anion]]s 
| {{{Other_anion}}} 
|-
| Other [[Ion|cation]]s 
| {{{Ohter_cation}}} 
|-
| Related compounds

| {{{Relative_Compounds}}}
|-
| {{chembox header}} | <small>Except where noted otherwise, data are given for<br /> materials in their [[standard state|standard state (at 25 °C, 100 kPa)]]<br />[[wikipedia:Chemical infobox|Infobox disclaimer and references]]</small>
|-
|}
{{Chem-Data_Structure}}

Template:Chem-Data

2006-12-08T15:38:04Z

Rih05:

<noinclude>

</noinclude>{| class="toccolours" border="1" style="float: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse; width: 280px"
! {{chembox header}} | {{PAGENAME}} 
|-
| align="center" colspan="2" bgcolor="#ffffff" | [[Image:{{PAGENAME}}.jpg|200px|{{PAGENAME}}]] 
|-
! {{chembox header}} | General
|-
| [http://en.wikipedia.org/wiki/IUPAC Systematic name]
| {{{IUPACName}}}

|-
| Other names
| {{{OtherNames}}}
|-
| [http://en.wikipedia.org/wiki/Chemical_formula Molecular formula]
| {{{Formula}}}
|-
| [http://en.wikipedia.org/wiki/Chemical_file_format SMILES] 
| {{{SMILES}}}
|-
| [http://en.wikipedia.org/wiki/Molar_mass Molar mass]
| {{{MolarMass}}}
|-
| Appearance
| {{{Appearance}}}
|-
| [http://en.wikipedia.org/wiki/CAS_registry_number CAS number]
| {{{CASNo}}}
|-
! {{chembox header}} | Properties
|-
| [http://en.wikipedia.org/wiki/Density Density] & [http://en.wikipedia.org/wiki/Phase_%28matter%29 phase]
| {{{Density}}} g/cm³ 
|-
| Solubility in water
| {{{Sol_Water}}} g/100 ml (25°C) 
|-



| Melting point
| {{{Mp}}} K 
|-
| [Boiling point]
| {{{Bp}}} K
|-
| [Acid dissociation constant|Acidity]] (p''K''<sub>a</sub>) 
| {{{pKa}}}
|-
| [[Acid dissociation constant|Basicity]] (p''K''<sub>b</sub>) 
| {{{pKb}}}
|-
| [[Specific rotation|Chiral rotation <nowiki>[α]</nowiki><sub>D</sub>]] 
| {{{Rotation}}}°
|-
| [[Viscosity]]
| {{{Viscosity}}} [[Poise|cP]] at 25°C 
|-
! {{chembox header}} | Structure
|-
| [[Orbital_hybridisation#Molecule_shape|Molecular shape]] 
| {{{Mol_Shape}}} 
|-
| [[Coordination geometry|Coordination<br />geometry]] 
| {{{Coordination}}} 
|-
| [[Crystal structure]] 
| {{{Crystal_Structure}}} 
|-
| [[Dipole#Molecular_dipoles|Dipole moment]]
| {{{DM}}} [[Debye|D]]
|-
! {{chembox header}} | Hazards 
|-
| [[Material safety data sheet|MSDS]]
| [[{{PAGENAME}} (data page)#Material Safety Data Sheet|External MSDS]] 
|-
| Main [[Worker safety and health|hazard]]s
| {{{Hazards}}} 
|-
| [[NFPA 704]]
| {{{NFPA}}}
|-
| [[Flash point]]
| {{{Fp}}}°C
|-
| [[Risk and Safety Statements|R/S statement]]
| [[List of R-phrases|R]]: {{{R-S}}} <br /> [[List of S-phrases|S]]: ?
|-
| [[RTECS]] number
| {{{RTECS}}}
|-
! {{chembox header}} | [[{{PAGENAME}} (data page)|Supplementary data page]]
|-
| [[{{PAGENAME}} (data page)#Structure and properties|Structure and<br />properties]]
| [http://en.wikipedia.org/wiki/Refractive_index ''n''], [http://en.wikipedia.org/wiki/Dielectric_constant ε<sub>r</sub>], etc.
|-
| [[{{PAGENAME}} (data page)#Thermodynamic properties|Thermodynamic<br />data]]
| Phase behaviour<br />Solid, liquid, gas
|-
| [[{{PAGENAME}} (data page)#Spectral data|Spectral data]]
| [[UV/VIS spectroscopy|UV]], [[Infrared spectroscopy|IR]], [[nuclear magnetic resonance spectroscopy|NMR]], [[Mass spectrometry|MS]]
|-
! {{chembox header}} | Related compounds
|-
| Other [[Ion|anion]]s 
| {{{Other_anion}}} 
|-
| Other [[Ion|cation]]s 
| {{{Ohter_cation}}} 
|-
| Related compounds

| {{{Relative_Compounds}}}
|-
| {{chembox header}} | <small>Except where noted otherwise, data are given for<br /> materials in their [[standard state|standard state (at 25 °C, 100 kPa)]]<br />[[wikipedia:Chemical infobox|Infobox disclaimer and references]]</small>
|-
|}
{{Chem-Data_Structure}}

Template:Chem-Data

2006-12-08T15:34:48Z

Rih05:

<noinclude>

</noinclude>{| class="toccolours" border="1" style="float: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse; width: 280px"
! {{chembox header}} | {{PAGENAME}} 
|-
| align="center" colspan="2" bgcolor="#ffffff" | [[Image:{{PAGENAME}}.jpg|200px|{{PAGENAME}}]] 
|-
! {{chembox header}} | General
|-
| [http://en.wikipedia.org/wiki/IUPAC Systematic name]
| {{{IUPACName}}}

|-
| Other names
| {{{OtherNames}}}
|-
| [http://en.wikipedia.org/wiki/Chemical_formula Molecular formula]
| {{{Formula}}}
|-
| [http://en.wikipedia.org/wiki/Chemical_file_format SMILES] 
| {{{SMILES}}}
|-
| Molar mass
| {{{MolarMass}}}
|-
| Appearance
| {{{Appearance}}}
|-
| CAS number
| {{{CASNo}}}
|-
! {{chembox header}} | Properties
|-
| Density and phase
| {{{Density}}} g/cm³ 
|-
| Solubility in water
| {{{Sol_Water}}} g/100 ml (25°C) 
|-



| Melting point
| {{{Mp}}} K 
|-
| [Boiling point]
| {{{Bp}}} K
|-
| [Acid dissociation constant|Acidity]] (p''K''<sub>a</sub>) 
| {{{pKa}}}
|-
| [[Acid dissociation constant|Basicity]] (p''K''<sub>b</sub>) 
| {{{pKb}}}
|-
| [[Specific rotation|Chiral rotation <nowiki>[α]</nowiki><sub>D</sub>]] 
| {{{Rotation}}}°
|-
| [[Viscosity]]
| {{{Viscosity}}} [[Poise|cP]] at 25°C 
|-
! {{chembox header}} | Structure
|-
| [[Orbital_hybridisation#Molecule_shape|Molecular shape]] 
| {{{Mol_Shape}}} 
|-
| [[Coordination geometry|Coordination<br />geometry]] 
| {{{Coordination}}} 
|-
| [[Crystal structure]] 
| {{{Crystal_Structure}}} 
|-
| [[Dipole#Molecular_dipoles|Dipole moment]]
| {{{DM}}} [[Debye|D]]
|-
! {{chembox header}} | Hazards 
|-
| [[Material safety data sheet|MSDS]]
| [[{{PAGENAME}} (data page)#Material Safety Data Sheet|External MSDS]] 
|-
| Main [[Worker safety and health|hazard]]s
| {{{Hazards}}} 
|-
| [[NFPA 704]]
| {{{NFPA}}}
|-
| [[Flash point]]
| {{{Fp}}}°C
|-
| [[Risk and Safety Statements|R/S statement]]
| [[List of R-phrases|R]]: {{{R-S}}} <br /> [[List of S-phrases|S]]: ?
|-
| [[RTECS]] number
| {{{RTECS}}}
|-
! {{chembox header}} | [[{{PAGENAME}} (data page)|Supplementary data page]]
|-
| [[{{PAGENAME}} (data page)#Structure and properties|Structure and<br />properties]]
| [http://en.wikipedia.org/wiki/Refractive_index ''n''], [http://en.wikipedia.org/wiki/Dielectric_constant ε<sub>r</sub>], etc.
|-
| [[{{PAGENAME}} (data page)#Thermodynamic properties|Thermodynamic<br />data]]
| Phase behaviour<br />Solid, liquid, gas
|-
| [[{{PAGENAME}} (data page)#Spectral data|Spectral data]]
| [[UV/VIS spectroscopy|UV]], [[Infrared spectroscopy|IR]], [[nuclear magnetic resonance spectroscopy|NMR]], [[Mass spectrometry|MS]]
|-
! {{chembox header}} | Related compounds
|-
| Other [[Ion|anion]]s 
| {{{Other_anion}}} 
|-
| Other [[Ion|cation]]s 
| {{{Ohter_cation}}} 
|-
| Related compounds

| {{{Relative_Compounds}}}
|-
| {{chembox header}} | <small>Except where noted otherwise, data are given for<br /> materials in their [[standard state|standard state (at 25 °C, 100 kPa)]]<br />[[wikipedia:Chemical infobox|Infobox disclaimer and references]]</small>
|-
|}
{{Chem-Data_Structure}}

Template:Chem-Data

2006-12-08T15:29:27Z

Rih05:

<noinclude>

</noinclude>{| class="toccolours" border="1" style="float: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse; width: 280px"
! {{chembox header}} | {{PAGENAME}} 
|-
| align="center" colspan="2" bgcolor="#ffffff" | [[Image:{{PAGENAME}}.jpg|200px|{{PAGENAME}}]] 
|-
! {{chembox header}} | General
|-
| Systematic name
| {{{IUPACName}}}

|-
| Other names
| {{{OtherNames}}}
|-
| Molecular formula
| {{{Formula}}}
|-
| SMILES 
| {{{SMILES}}}
|-
| Molar mass
| {{{MolarMass}}}
|-
| Appearance
| {{{Appearance}}}
|-
| CAS number
| {{{CASNo}}}
|-
! {{chembox header}} | Properties
|-
| Density and phase
| {{{Density}}} g/cm³ 
|-
| Solubility in water
| {{{Sol_Water}}} g/100 ml (25°C) 
|-



| Melting point
| {{{Mp}}} K 
|-
| [[Boiling point]]
| {{{Bp}}} K
|-
| [[Acid dissociation constant|Acidity]] (p''K''<sub>a</sub>) 
| {{{pKa}}}
|-
| [[Acid dissociation constant|Basicity]] (p''K''<sub>b</sub>) 
| {{{pKb}}}
|-
| [[Specific rotation|Chiral rotation <nowiki>[α]</nowiki><sub>D</sub>]] 
| {{{Rotation}}}°
|-
| [[Viscosity]]
| {{{Viscosity}}} [[Poise|cP]] at 25°C 
|-
! {{chembox header}} | Structure
|-
| [[Orbital_hybridisation#Molecule_shape|Molecular shape]] 
| {{{Mol_Shape}}} 
|-
| [[Coordination geometry|Coordination<br />geometry]] 
| {{{Coordination}}} 
|-
| [[Crystal structure]] 
| {{{Crystal_Structure}}} 
|-
| [[Dipole#Molecular_dipoles|Dipole moment]]
| {{{DM}}} [[Debye|D]]
|-
! {{chembox header}} | Hazards 
|-
| [[Material safety data sheet|MSDS]]
| [[{{PAGENAME}} (data page)#Material Safety Data Sheet|External MSDS]] 
|-
| Main [[Worker safety and health|hazard]]s
| {{{Hazards}}} 
|-
| [[NFPA 704]]
| {{{NFPA}}}
|-
| [[Flash point]]
| {{{Fp}}}°C
|-
| [[Risk and Safety Statements|R/S statement]]
| [[List of R-phrases|R]]: {{{R-S}}} <br /> [[List of S-phrases|S]]: ?
|-
| [[RTECS]] number
| {{{RTECS}}}
|-
! {{chembox header}} | [[{{PAGENAME}} (data page)|Supplementary data page]]
|-
| [[{{PAGENAME}} (data page)#Structure and properties|Structure and<br />properties]]
| [http://en.wikipedia.org/wiki/Refractive_index ''n''], [http://en.wikipedia.org/wiki/Dielectric_constant ε<sub>r</sub>], etc.
|-
| [[{{PAGENAME}} (data page)#Thermodynamic properties|Thermodynamic<br />data]]
| Phase behaviour<br />Solid, liquid, gas
|-
| [[{{PAGENAME}} (data page)#Spectral data|Spectral data]]
| [[UV/VIS spectroscopy|UV]], [[Infrared spectroscopy|IR]], [[nuclear magnetic resonance spectroscopy|NMR]], [[Mass spectrometry|MS]]
|-
! {{chembox header}} | Related compounds
|-
| Other [[Ion|anion]]s 
| {{{Other_anion}}} 
|-
| Other [[Ion|cation]]s 
| {{{Ohter_cation}}} 
|-
| Related compounds

| {{{Relative_Compounds}}}
|-
| {{chembox header}} | <small>Except where noted otherwise, data are given for<br /> materials in their [[standard state|standard state (at 25 °C, 100 kPa)]]<br />[[wikipedia:Chemical infobox|Infobox disclaimer and references]]</small>
|-
|}
{{Chem-Data_Structure}}

Template:Drug-Box

2006-12-08T15:20:38Z

Rih05:

{| style="float: right; clear: right; margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" align="right" width="300"
! colspan="2" align="center" bgcolor="#dddddd"| {{{Box_Name}}} 
|-
| align="center" colspan="2" bgcolor="#ffffff" | [[Image:{{{ImageFile}}}|250px|{{{Box_Name}}}]] 
|-
! colspan="2" align="center" bgcolor="#dddddd"|IUPAC Systematic name
|-
| colspan="2" align="center"| {{{IUPACName}}}
|-
! colspan="2" align="center" bgcolor="#dddddd"| Other name
|-
| colspan="2" align="center"| [http://www.google.co.uk/search?hl=en&q={{{OtherName}}}&btnG=Google+Search&meta= {{{OtherName}}}]
|-
! colspan="2" align="center" bgcolor="#dddddd"|Indentifiers
|-
! align="left" bgcolor="#ddeeff" width="120"|[http://en.wikipedia.org/wiki/ATC_code ATC Code]
| align="center"| {{{ATC_Code}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/CAS_number CAS number]
| align="center"|{{{CASNo}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/PubChem PubChem (CID)]
| align="center"|[http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid={{{PubChem}}} {{{PubChem}}}]
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Simplified_molecular_input_line_entry_specification SMILES]
| align="center"|[http://www.emolecules.com/cgi-bin/search?t=ss&q={{{SMILES}}} {{{SMILES}}}]
|-
! colspan="2" align="center" bgcolor="#dddddd"| Chemical Data
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Chemical_formula Molecular formula]
| align="center"|{{{Formula}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Molecular_weight Molar mass]
| align="center"|{{{MolarMass}}} g/mol
|-
! colspan="2" align="center" bgcolor="#dddddd"| Pharmacokinetic Data
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Bioavailability Bioavailability]
| align="center"|{{{Bioavailability}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Plasma_protein_binding Protein Binding]
| align="center"|{{{Protein_binding}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Metabolism Metabolism]
| align="center"|{{{Metabolism}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Elimination_half-life Half life]
| align="center"|{{{Half_life}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Excretion Excretion]
| align="center"|{{{Excretion}}}
|-
! colspan="2" align="center" bgcolor="#dddddd"| Therapeutic considerations
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Pregnancy_category Pregnancy cat.]
| align="center"|{{{Pregnancy_cat}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods Legal status]
| align="center"|{{{Legal_status}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Route_of_administration Routes]
| align="center"|{{{Routes}}}
|-

|}

<noinclude>
*This box is designed as such that all you need to do is plug the below code into your page and place your data after the '=' for each variable, SI units for measurments will automatically be added.
*For further information on the variables click the tag of interest and follow link to Wiki description page
*Items such as the identifiers are set up to use the entered data to link to sites such as Emolecules, Google and PubChem giving further information about the molecule. For these boxes just one valaue should be entered (e.g. One SMILE string or one Pub Chem code
<pre>
{{Drug-Box |
| Box_Name = this is the title of your box
| ImageFile = example_image.jpg
| IUPACName = official chemical identifier name
| OtherName = other trade names
| CAS_No =
| ATC_Code =
| PubChem =
| SMILES = surround in nowiki script code '<' nowiki'>' insert SMILE here'</'nowiki'>'
| Formula = e.g.(C<sub>2</sub>H<sub>4</sub>)
| MolarMass = Molecular mass
| Bioavailability =
| Protein_binding
| Metabolism =
| Half_life =
| Excretion =
| Pregnancy_cat =
| Legal_status =
| Routes =
}}
</pre>
</noinclude>
<noinclude>*For Further Details have a chat with --[[User:Rih05|Rih05]]
*For usage example see [[It:sitagliptin_page]]
</noinclude>

It:sitagliptin page

2006-12-08T15:15:49Z

Rih05: /* References */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

==Structure of Sitgliptin==
===3D Structures of Sitagliptin===
<div align="center">
In order to see the 3D structure in anaglyph 3D mode, special Red/Blue anaglyph glassess will be needed.

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
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<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
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REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

*The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====Dosage Forms and Strengths====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.<br>Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.<br>Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
*Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

*Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]
* [http://www.glucagon.com/JanuviaProductInsertOctober2006.pdf Januvia Product Insert]
* [http://www.medicalnewstoday.com/medicalnews.php?newsid=25962 Medical News today]
* [http://www.glucagon.com/JANUVIAUSPPatientinformationOct-06.pdf Patient Information Sheet]

It:sitagliptin page

2006-12-08T15:15:00Z

Rih05: /* References */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

==Structure of Sitgliptin==
===3D Structures of Sitagliptin===
<div align="center">
In order to see the 3D structure in anaglyph 3D mode, special Red/Blue anaglyph glassess will be needed.

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
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|-
|}
</div>

==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

*The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====Dosage Forms and Strengths====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.<br>Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.<br>Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
*Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

*Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]
* [http://www.glucagon.com/JanuviaProductInsertOctober2006.pdf Januvia Product Insert]
* [http://www.medicalnewstoday.com/medicalnews.php?newsid=25962 Medical News today]

Template:Drug-Box

2006-12-08T15:12:16Z

Rih05:

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|-
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|-
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| align="center"|{{{Formula}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Molecular_weight Molar mass]
| align="center"|{{{MolarMass}}} g/mol
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! colspan="2" align="center" bgcolor="#dddddd"| Pharmacokinetic Data
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| align="center"|{{{Bioavailability}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Plasma_protein_binding Protein Binding]
| align="center"|{{{Protein_binding}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Metabolism Metabolism]
| align="center"|{{{Metabolism}}}
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! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Elimination_half-life Half life]
| align="center"|{{{Half_life}}}
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| align="center"|{{{Excretion}}}
|-
! colspan="2" align="center" bgcolor="#dddddd"| Therapeutic considerations
|-
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| align="center"|{{{Routes}}}
|-

|}

<noinclude>
*This box is designed as such that all you need to do is plug the below code into your page and place your data after the '=' for each variable, SI units for measurments will automatically be added.
*For further information on the variables click the tag of interest and follow link to Wiki description page
<pre>
{{Drug-Box |
| Box_Name = this is the title of your box
| ImageFile = example_image.jpg
| IUPACName = official chemical identifier name
| OtherName = other trade names
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| Protein_binding
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<noinclude>*For Further Details have a chat with --[[User:Rih05|Rih05]]
*For usage example see [[It:sitagliptin_page]]
</noinclude>

Template:Drug-Box

2006-12-08T15:11:05Z

Rih05:

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|-
| align="center" colspan="2" bgcolor="#ffffff" | [[Image:{{{ImageFile}}}|250px|{{{Box_Name}}}]] 
|-
! colspan="2" align="center" bgcolor="#dddddd"|IUPAC Systematic name
|-
| colspan="2" align="center"| {{{IUPACName}}}
|-
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|-
! colspan="2" align="center" bgcolor="#dddddd"|Indentifiers
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! align="left" bgcolor="#ddeeff" width="120"|[http://en.wikipedia.org/wiki/ATC_code ATC Code]
| align="center"| {{{ATC_Code}}}
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| align="center"|{{{CASNo}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/PubChem PubChem (CID)]
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|-
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|-
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| align="center"|{{{MolarMass}}} g/mol
|-
! colspan="2" align="center" bgcolor="#dddddd"| Pharmacokinetic Data
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Bioavailability Bioavailability]
| align="center"|{{{Bioavailability}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Plasma_protein_binding Protein Binding]
| align="center"|{{{Protein_binding}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Metabolism Metabolism]
| align="center"|{{{Metabolism}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Elimination_half-life Half life]
| align="center"|{{{Half_life}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Excretion Excretion]
| align="center"|{{{Excretion}}}
|-
! colspan="2" align="center" bgcolor="#dddddd"| Therapeutic considerations
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Pregnancy_category Pregnancy cat.]
| align="center"|{{{Pregnancy_cat}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods Legal status]
| align="center"|{{{Legal_status}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Route_of_administration Routes]
| align="center"|{{{Routes}}}
|-

|}

<noinclude>
*This box is designed as such that all you need to do is plug the below code into your page and place your data after the '=' for each variable, SI units for measurments will automatically be added.
*For further information on the variables click the tag of interest and follow link to Wiki description page
<pre>
{{Drug-Box |
| Box_Name = this is the title of your box
| ImageFile = example_image.jpg
| IUPACName = official chemical identifier name
| OtherName = other trade names
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| MolarMass = Molecular mass
| Bioavailability =
| Protein_binding
| Metabolism =
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| Excretion =
| Pregnancy_cat =
| Legal_status =
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}}
</pre>
</noinclude>
<noinclude>*For Further Details have a chat with --[[User:Rih05|Rih05]]
*For usage example see [[sitagliptin_page]]
</noinclude>

Template:Drug-Box

2006-12-08T15:09:36Z

Rih05:

{| style="float: right; clear: right; margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" align="right" width="300"
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| align="center" colspan="2" bgcolor="#ffffff" | [[Image:{{{ImageFile}}}|250px|{{{Box_Name}}}]] 
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| colspan="2" align="center"| {{{IUPACName}}}
|-
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|-
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|-
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| align="center"| {{{ATC_Code}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/CAS_number CAS number]
| align="center"|{{{CASNo}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/PubChem PubChem (CID)]
| align="center"|[http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid={{{PubChem}}} {{{PubChem}}}]
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Simplified_molecular_input_line_entry_specification SMILES]
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|-
! colspan="2" align="center" bgcolor="#dddddd"| Chemical Data
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Chemical_formula Molecular formula]
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|-
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| align="center"|{{{MolarMass}}} g/mol
|-
! colspan="2" align="center" bgcolor="#dddddd"| Pharmacokinetic Data
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Bioavailability Bioavailability]
| align="center"|{{{Bioavailability}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Plasma_protein_binding Protein Binding]
| align="center"|{{{Protein_binding}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Metabolism Metabolism]
| align="center"|{{{Metabolism}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Elimination_half-life Half life]
| align="center"|{{{Half_life}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Excretion Excretion]
| align="center"|{{{Excretion}}}
|-
! colspan="2" align="center" bgcolor="#dddddd"| Therapeutic considerations
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Pregnancy_category Pregnancy cat.]
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|-
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|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Route_of_administration Routes]
| align="center"|{{{Routes}}}
|-

|}

<noinclude>
*This box is designed as such that all you need to do is plug the below code into your page and place your data after the '=' for each variable, SI units for measurments will automatically be added.
*For further information on the variables click the tag of interest and follow link to Wiki description page
<pre>
{{Drug-Box |
| Box_Name = this is the title of your box
| ImageFile = example_image.jpg
| IUPACName = official chemical identifier name
| OtherName = other trade names
| CAS_No =
| ATC_Code =
| PubChem =
| SMILES = surround in nowiki script code '<' nowiki'>' insert SMILE here'</'nowiki'>'
| Formula = e.g.(C<sub>2</sub>H<sub>4</sub>)
| MolarMass = Molecular mass
| Bioavailability =
| Protein_binding
| Metabolism =
| Half_life =
| Excretion =
| Pregnancy_cat =
| Legal_status =
| Routes =
}}
</pre>
</noinclude>
<noinclude>For Further Details have a chat with --[[User:Rih05|Rih05]]</noinclude>

Template:Drug-Box

2006-12-08T15:08:59Z

Rih05:

{| style="float: right; clear: right; margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" align="right" width="300"
! colspan="2" align="center" bgcolor="#dddddd"| {{{Box_Name}}} 
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| align="center" colspan="2" bgcolor="#ffffff" | [[Image:{{{ImageFile}}}|250px|{{{Box_Name}}}]] 
|-
! colspan="2" align="center" bgcolor="#dddddd"|IUPAC Systematic name
|-
| colspan="2" align="center"| {{{IUPACName}}}
|-
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|-
! colspan="2" align="center" bgcolor="#dddddd"|Indentifiers
|-
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| align="center"| {{{ATC_Code}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/CAS_number CAS number]
| align="center"|{{{CASNo}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/PubChem PubChem (CID)]
| align="center"|[http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid={{{PubChem}}} {{{PubChem}}}]
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Simplified_molecular_input_line_entry_specification SMILES]
| align="center"|[http://www.emolecules.com/cgi-bin/search?t=ss&q={{{SMILES}}} {{{SMILES}}}]
|-
! colspan="2" align="center" bgcolor="#dddddd"| Chemical Data
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Chemical_formula Molecular formula]
| align="center"|{{{Formula}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Molecular_weight Molar mass]
| align="center"|{{{MolarMass}}} g/mol
|-
! colspan="2" align="center" bgcolor="#dddddd"| Pharmacokinetic Data
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Bioavailability Bioavailability]
| align="center"|{{{Bioavailability}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Plasma_protein_binding Protein Binding]
| align="center"|{{{Protein_binding}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Metabolism Metabolism]
| align="center"|{{{Metabolism}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Elimination_half-life Half life]
| align="center"|{{{Half_life}}}
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Excretion Excretion]
| align="center"|{{{Excretion}}}
|-
! colspan="2" align="center" bgcolor="#dddddd"| Therapeutic considerations
|-
! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Pregnancy_category Pregnancy cat.]
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! align="left" bgcolor="#ddeeff" width="120"| [http://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods Legal status]
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|-
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| align="center"|{{{Routes}}}
|-

|}

<noinclude>
*This box is designed as such that all you need to do is plug the below code into your page and place you data after the '=' for each variable, SI units for measurments will automatically be added.
*For further information on the variables click the tag of interest and follow link to Wiki description page
<pre>
{{Drug-Box |
| Box_Name = this is the title of your box
| ImageFile = example_image.jpg
| IUPACName = official chemical identifier name
| OtherName = other trade names
| CAS_No =
| ATC_Code =
| PubChem =
| SMILES = surround in nowiki script code '<' nowiki'>' insert SMILE here'</'nowiki'>'
| Formula = e.g.(C<sub>2</sub>H<sub>4</sub>)
| MolarMass = Molecular mass
| Bioavailability =
| Protein_binding
| Metabolism =
| Half_life =
| Excretion =
| Pregnancy_cat =
| Legal_status =
| Routes =
}}
</pre>
</noinclude>
<noinclude>For Further Details have a chat with --[[User:Rih05|Rih05]]</noinclude>

It:sitagliptin page

2006-12-08T14:53:05Z

Rih05: /* 3D Structures of Sitagliptin */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

==Structure of Sitgliptin==
===3D Structures of Sitagliptin===
<div align="center">
In order to see the 3D structure in anaglyph 3D mode, special Red/Blue anaglyph glassess will be needed.

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
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REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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|-
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</div>

==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

*The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====Dosage Forms and Strengths====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.<br>Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.<br>Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
*Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

*Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:52:23Z

Rih05: /* 3D Structures of Sitagliptin */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

==Structure of Sitgliptin==
===3D Structures of Sitagliptin===
<div align="left">
In order to see the 3D structure in anaglyph 3D mode, special Red/Blue anaglyph glassess will be needed.

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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<script>spin off</script>
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</jmolButton>

</jmol>

|-
|}
</div>

==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

*The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====Dosage Forms and Strengths====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.<br>Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.<br>Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
*Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

*Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:51:59Z

Rih05: /* Side effects */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

==Structure of Sitgliptin==
===3D Structures of Sitagliptin===
<div align="center">
In order to see the 3D structure in anaglyph 3D mode, special Red/Blue anaglyph glassess will be needed.

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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</jmol>

|-
|}
</div>

==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

*The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====Dosage Forms and Strengths====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.<br>Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.<br>Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
*Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

*Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:47:10Z

Rih05: /* 3D Structures of Sitagliptin */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===
<div align="center">
In order to see the 3D structure in anaglyph 3D mode, special Red/Blue anaglyph glassess will be needed.

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
</jmolApplet>
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|-
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</div>

==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

*The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====Dosage Forms and Strengths====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.<br>Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.<br>Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
*Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

*Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:46:41Z

Rih05: /* 3D Structures of Sitagliptin */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===
In order to see the 3D structure in anaglyph 3D mode, special Red/Blue anaglyph glassess will be needed.
<div align="center">

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
</jmolApplet>
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|-
|}
</div>

==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

*The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====Dosage Forms and Strengths====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.<br>Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.<br>Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
*Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

*Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:44:30Z

Rih05: /* Pharmakinetics */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===
<div align="center">

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
</jmolApplet>
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|}
</div>

==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

*The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====Dosage Forms and Strengths====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.<br>Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.<br>Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
*Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

*Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:44:16Z

Rih05: /* Metabolism */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===
<div align="center">

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
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REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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</div>

==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

*The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====Dosage Forms and Strengths====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.<br>Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
*Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

*Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:42:51Z

Rih05: /* 3D Structures of Sitagliptin */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===
<div align="center">

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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|-
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</div>

==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

*The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====Dosage Forms and Strengths====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.<br><br>Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
*Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

*Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:41:36Z

Rih05: /* What is Sitagliptin? */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===
<div align="center">

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
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<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

*The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====Dosage Forms and Strengths====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.<br><br>Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
*Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

*Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:41:12Z

Rih05: /* 3D Structures of Sitagliptin */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===
<div align="center">

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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|-
|}

==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

*The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====Dosage Forms and Strengths====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.<br><br>Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
*Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

*Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:39:51Z

Rih05: /* Dosage and Administration */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
</jmolApplet>
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|-
|}

==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

*The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====Dosage Forms and Strengths====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.<br><br>Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
*Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

*Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:39:20Z

Rih05: /* Metabolism */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
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<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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|-
|}

==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====Dosage Forms and Strengths====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.<br><br>Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
*Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

*Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:38:50Z

Rih05: /* Metabolism */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
</jmolApplet>
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|-
|}

==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====Dosage Forms and Strengths====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.
Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
*Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

*Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:38:27Z

Rih05: /* Metabolism */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
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<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
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REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====Dosage Forms and Strengths====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
*Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

*Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:37:46Z

Rih05: /* Excretion */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====Dosage Forms and Strengths====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
*Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

*Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:37:34Z

Rih05: /* DOSAGE FORMS AND STRENGTHS */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====Dosage Forms and Strengths====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:36:38Z

Rih05: /* Dosage and Administration */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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|-
|}

==Pharmaceutical Information==

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====DOSAGE FORMS AND STRENGTHS====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:35:41Z

Rih05: /* Dosage and Administration */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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|-
|}

===Dosage and Administration===

[[Image:tablets.jpg|frame|Januvia Tablets]]

The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====DOSAGE FORMS AND STRENGTHS====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:34:56Z

Rih05: /* What is Sitagliptin? */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
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REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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|-
|}

===Dosage and Administration===
The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====DOSAGE FORMS AND STRENGTHS====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:34:04Z

Rih05: /* Brief Definition : */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
<div align="center">
[[Image:tablets.jpg|Januvia Tablets]]
</div>

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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|}

===Dosage and Administration===
The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====DOSAGE FORMS AND STRENGTHS====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T14:31:47Z

Rih05: /* Brief Definition : */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
<div align="center">
[[Image:tablets.jpg|Januvia Tablets]]
</div>

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
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<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
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REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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===Dosage and Administration===
The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====DOSAGE FORMS AND STRENGTHS====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T12:02:07Z

Rih05:

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
<div align="center">
[[Image:tablets.jpg|Januvia Tablets]]
</div>

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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===Dosage and Administration===
The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====DOSAGE FORMS AND STRENGTHS====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T12:01:42Z

Rih05: /* What is Sitagliptin? */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
<div align="left">
[[Image:tablets.jpg|Januvia Tablets]]
</div>

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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|-
|}

===Dosage and Administration===
The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====DOSAGE FORMS AND STRENGTHS====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T12:01:31Z

Rih05: /* What is Sitagliptin? */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
<div align="left">
[[Image:tablets.jpg|Januvia Tablets]]
</div>

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
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<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
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REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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|-
|}

===Dosage and Administration===
The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====DOSAGE FORMS AND STRENGTHS====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T12:00:31Z

Rih05: /* What is Sitagliptin? */

==Sitagliptin ( active Januvia <sup>tm</sup> ingredient)==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Sitagliptin
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

<div align="left">
[[Image:tablets.jpg]]
</div>

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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|}

===Dosage and Administration===
The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====DOSAGE FORMS AND STRENGTHS====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T11:56:59Z

Rih05: /* Brief Definition : */

==Sitagliptin ( active Januvia <sup>tm</sup> ingredient)==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Sitagliptin
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
<div align="right">
[[Image:tablets.jpg|thumb|Januvia Tablets]]
</div>

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
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REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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===Dosage and Administration===
The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====DOSAGE FORMS AND STRENGTHS====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T11:56:42Z

Rih05: /* Sitagliptin ( Januvia <sup>tm</sup> ) */

==Sitagliptin ( active Januvia <sup>tm</sup> ingredient)==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
<div align="right">
[[Image:tablets.jpg|thumb|Januvia Tablets]]
</div>

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
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REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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===Dosage and Administration===
The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====DOSAGE FORMS AND STRENGTHS====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T11:53:44Z

Rih05: /* What is Sitagliptin? */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
<div align="right">
[[Image:tablets.jpg|thumb|Januvia Tablets]]
</div>

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
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<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
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REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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===Dosage and Administration===
The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====DOSAGE FORMS AND STRENGTHS====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T11:51:45Z

Rih05: /* What is Sitagliptin? */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
<div align="right">
[[Image:tablets.jpg]]
</div>

The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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===Dosage and Administration===
The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====DOSAGE FORMS AND STRENGTHS====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T11:48:08Z

Rih05: /* What is Sitagliptin? */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
<div align="center">
[[Image:tablets.jpg]]
</div>

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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|-
|}

===Dosage and Administration===
The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====DOSAGE FORMS AND STRENGTHS====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T11:47:22Z

Rih05: /* What is Sitagliptin? */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

[[Image:tablets.jpg]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
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REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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===Dosage and Administration===
The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====DOSAGE FORMS AND STRENGTHS====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T11:46:41Z

Rih05: /* What is Sitagliptin? */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

[[Image:tablets.jpg|thumb|Januvia tablets]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

{| style="margin: 0 0 0.5em 1em; background: #ffffff;" class="toccolours" border="0" cellpadding="1" width="300"
! Jmol Structure
|-
|
<jmol>
<jmolApplet>
<size>450</size>
<color>black</color>
<script>zoom 100; ball and stick on;frame 1; move 10 -20 10 0 0 0 0 0 3; delay 1; spin on;</script>
<inlineContents>REMARK MSI WebLab Viewer PDB file
REMARK Created: Tue Oct 24 14:17:29 GMT Standard Time 2006
ATOM 1 C1 MOL 1 24.957 10.890 0.016 1.00 0.00
ATOM 2 F2 MOL 1 26.264 11.134 0.388 1.00 0.00
ATOM 3 F3 MOL 1 24.944 10.366 -1.258 1.00 0.00
ATOM 4 F4 MOL 1 24.365 9.961 0.849 1.00 0.00
ATOM 5 C5 MOL 1 24.174 12.186 0.005 1.00 0.00
ATOM 6 N6 MOL 1 22.802 12.351 -0.016 1.00 0.00
ATOM 7 N7 MOL 1 24.712 13.343 0.019 1.00 0.00
ATOM 8 C8 MOL 1 22.591 13.676 -0.008 1.00 0.00
ATOM 9 C9 MOL 1 21.763 11.357 -0.082 1.00 0.00
ATOM 10 N10 MOL 1 23.710 14.285 0.011 1.00 0.00
ATOM 11 C11 MOL 1 21.250 14.327 -0.014 1.00 0.00
ATOM 12 C12 MOL 1 20.441 11.943 0.520 1.00 0.00
ATOM 13 N13 MOL 1 20.176 13.311 -0.004 1.00 0.00
ATOM 14 C14 MOL 1 18.820 13.806 -0.170 1.00 0.00
ATOM 15 C15 MOL 1 17.591 12.930 0.007 1.00 0.00
ATOM 16 O16 MOL 1 18.664 14.997 -0.458 1.00 0.00
ATOM 17 C17 MOL 1 16.321 13.848 -0.031 1.00 0.00
ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
ATOM 19 N19 MOL 1 16.405 14.808 1.088 1.00 0.00
ATOM 20 C20 MOL 1 13.730 13.831 0.050 1.00 0.00
ATOM 21 C21 MOL 1 12.552 13.207 0.060 1.00 0.00
ATOM 22 C22 MOL 1 13.757 15.304 -0.005 1.00 0.00
ATOM 23 F23 MOL 1 12.509 11.868 0.106 1.00 0.00
ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
TER</inlineContents>
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|}

===Dosage and Administration===
The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====DOSAGE FORMS AND STRENGTHS====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]

It:sitagliptin page

2006-12-08T11:45:53Z

Rih05: /* What is Sitagliptin? */

==Sitagliptin ( Januvia <sup>tm</sup> )==
===Brief Definition :===
Sitagliptin is a relatively new drug (''Approved by FDA 17/10/2006'') used for treating type 2 Diabetes '''Diabetes Mellitus'''.
{{Drug-Box |
| Box_Name = Sitagliptin
| ImageFile = Sitagliptin_large.gif
| IUPACName = (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-4-(2,4,5-trifluorophenyl butan-1-one
| OtherName = Januvia
| CASNo = -
| ATC_Code = -
| PubChem = 4369359
| SMILES = <nowiki>FC1=CC(F)=C(F)C=C1C[C@@H]([N])CC(N2CC3=NN=C([C@@](F)(F)F)N3CC2)=O</nowiki>
| Formula = C<sub>16</sub>H<sub>15</sub>N<sub>5</sub>F<sub>6</sub>O
| MolarMass = 407.314
| Bioavailability = 87%
| Protein_binding = 38%
| Metabolism = Hepatic (CYP3A4- and CYP2C8-mediated)
| Half_life = 8 to 14 hours
| Excretion = Renal (80%)
| Pregnancy_cat = B (US)
| Legal_status = Rx-only
| Routes = Oral
}}

===What is Sitagliptin?===
The new drug to fight type 2 diabetes Sitagliptin has shown from the trials that it reduces glucose in blood, improves beta-cell function and can help patients control their weight.
This drug was only approved for use on type 2 diabetes on 17th October 2006.
The sitagliptin worked best to help patients with type 2 diabetes when added to metformin or TZDs. The drug helps to control inculin release due to beta-cell disfunction, and controls the production of glucose by the liver which is uncontrollable when there is alpha and beta cell disfunction. [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]

[[Image:tablets.jpg|frame|Januvia tablets]]

===How Sitagliptin works===
Sitagliptin is a DPP-4 inhibitor which is believed to slow the inactivation of incretin (a type of gastrointestinal hormones) hormones and the concentration of these particular hormones are actually increased by Januvia.
Incretin hormones (''see diagram 1''), including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. The source of the diabetic problem is that the enzyme DPP-4 inactivates these hormones which are necessary for the handling of glucose in the blood. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. JANUVIA increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
<div align="left">
[[Image:Incretin.JPG]]
</div>

===Side effects===
Although only a new drug the side effects that have been found when in phase 2 and 3 of testing are
*stuffy or runny nose and sore throat
*upper respiratory infections
*headaches [http://www.januvia.com/sitagliptin_phosphate/januvia/hcp/press/index.jsp [1]]
==Structure of Sitgliptin==
===3D Structures of Sitagliptin===

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ATOM 18 C18 MOL 1 15.023 12.995 0.095 1.00 0.00
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ATOM 24 C24 MOL 1 11.299 13.977 0.019 1.00 0.00
ATOM 25 C25 MOL 1 12.621 16.000 -0.036 1.00 0.00
ATOM 26 C26 MOL 1 11.334 15.307 -0.025 1.00 0.00
ATOM 27 F27 MOL 1 12.656 17.338 -0.077 1.00 0.00
ATOM 28 F28 MOL 1 10.190 16.014 -0.062 1.00 0.00
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===Dosage and Administration===
The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin or a PPARg agonist (e.g., thiazolidinediones). JANUVIA can be taken with or without food.

====Patients with Renal Insufficiency====

*For patients with mild renal insufficiency (creatinine clearance [CrCl] ³50 mL/min, approximately corresponding to serum creatinine levels of £1.7 mg/dL in men and £1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

*For patients with moderate renal insufficiency (CrCl ³30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to £3.0 mg/dL in men and >1.5 to £2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

*For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.

*Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See CLINICAL PHARMACOLOGY .]

====DOSAGE FORMS AND STRENGTHS====

*100 mg tablets are beige, round, film-coated tablets with "277" on one side.

*50 mg tablets are light beige, round, film-coated tablets with "112" on one side.

*25 mg tablets are pink, round, film-coated tablets with "221" on one side.

===Pharmakinetics===
*The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 mM·hr, Cmax was 950 nM, and apparent terminal half-life (t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

===Absorption===
*The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food
===Metabolism===
*Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

===Excretion===
Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

== Type 2 Diabetes ==
Type 2 diabetes is the most common form of diabetes. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Insulin is necessary for the body to be able to use sugar. Sugar is the basic fuel for the cells in the body, and insulin takes the sugar from the blood into the cells. When glucose builds up in the blood instead of going into cells, it can cause two problems:
*Right away, your cells may be starved for energy.
*Over time, high blood glucose levels may hurt your eyes, kidneys, nerves or heart.

==== Associated Conditions====
*Conditions associated with type 2 diabetes include hyperglycemia and hypoglycemia

==References==
* [http://www.diabetes.org/type-2-diabetes.jsp American Diabetes Associtation]
* [http://www.rxlist.com/cgi/generic4/januvia_ids.htm#D Internet Drug Index]