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Identification
- Summary
Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor used for the management of type 2 diabetes mellitus.
- Brand Names
- Janumet, Januvia, Ristaben, Steglujan, Tesavel, Velmetia, Xelevia, Zituvimet, Zituvio
- Generic Name
- Sitagliptin
- DrugBank Accession Number
- DB01261
- Background
Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor used in conjunction with diet and exercise to improve glycemic control in patients with type 2 diabetes mellitusLabel,4,1,2. The effect of this medication leads to glucose dependent increases in insulin and decreases in glucagon to improve control of blood sugarLabel,1. Sitagliptin was granted FDA approval on October 16, 20066.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Sitagliptin (DB01261)
- Weight
- Average: 407.3136
Monoisotopic: 407.118079357 - Chemical Formula
- C16H15F6N5O
- Synonyms
- Sitagliptin
- Sitagliptina
- Sitagliptine
- Sitagliptinum
- External IDs
- LEZ-763
- LEZ763
Pharmacology
- Indication
Sitagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is not used to treat type 1 diabetes or patients with a history of pancreatitis.9
It is also used in combination with metformin 8 or ertugliflozin.10
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used as adjunct in combination to manage Type 2 diabetes mellitus Combination Product in combination with: Ertugliflozin (DB11827) •••••••••••• ••••• Used as adjunct in combination to manage Type 2 diabetes mellitus Combination Product in combination with: Metformin (DB00331) •••••••••••• ••••• Adjunct therapy in management of Type 2 diabetes mellitus •••••••••••• ••••• - Contraindications & Blackbox Warnings
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Sitagliptin inhibits DPP-4 which leads to increased levels of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide(GIP), decreased levels of glucagon, and a stronger insulin response to glucoseLabel,4,1,2.
- Mechanism of action
Inhibition of DPP-4 by sitagliptin slows DPP-4 mediated inactivation of incretins like GLP-1 and GIPLabel,2. Incretins are released throughout the day and upregulated in response to meals as part of glucose homeostasisLabel,4. Reduced inhibition of incretins increase insulin synthesis and decrease glucagon release in a manner dependant on glucose concentrationsLabel,1. These effects lead to an overall increase in blood glucose control which is demonstrated by reduced glycosylated hemoglobin (HbA1c)Label,4.
Target Actions Organism ADipeptidyl peptidase 4 inhibitorHumans - Absorption
Sitagliptin is 87% orally bioavailable and taking it with or without food does not affect its pharmacokineticsLabel,4. Sitagliptin reaches maximum plasma concentration in 2 hours4.
- Volume of distribution
- Protein binding
- Metabolism
Sitagliptin is mostly not metabolised, with 79% of the dose excreted in the urine as the unchanged parent compoundLabel. Minor metabolic pathways are mediated mainly by cytochrome p450(CYP)3A4 and to a lesser extent by CYP2C8Label. After 18 hours, 81% of the dose has remained unchanged, while 2% has been N-sulfated to the M1 metabolite, 6% has been oxidatively desaturated and cyclized to the M2 metabolite, <1% glucuronidated at an unknown site to the M3 metabolite, <1% has been carbamoylated and glucuronidated to the M4 metabolite, 6% has been oxidatively saturated and cyclized to the M5 metabolite, and 2% has been hydroxylated at an unknown site to the M6 metabolite5. The M2 metabolite is the cis isomer while the M5 metabolite is the trans isomer of the same metabolite5.
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- Route of elimination
Approximately 79% of sitagliptin is excreted in the urine as the unchanged parent compoundLabel. 87% of the dose is eliminated in the urine and 13% in the fecesLabel,4.
- Half-life
Approximately 12.4 hoursLabel. Other studies have reported a half life of approximately 11 hours4.
- Clearance
- Adverse Effects
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Animal studies in pregnancy have shown no adverse effects on the mother or offspring at normal doses, however these results are not always applicable to humans. There is a voluntary fetal exposure registry Label,7. Animal studies at 100 times the maximum recommended human dose resulted in an increase in rib malformations. Sitagliptin is excreted in the milk of rats but it is not known if it would also be expressed in human breast milk. Because many drugs are expressed in human breast milk, the risk and benefit of prescribing the medication must be considered. There is currently a lack of safety and effectiveness data in pediatric patients. No differences in safety and efficacy were observed in geriatric patients compared to younger patients, however caution should be used in this population as they are more likely to have reduced renal functionLabel. Sitagliptin has also been associated with a 34% relative risk increase for all cause infection4. There was no significant difference in patient response across sex, age, race, ethnicity, and BMI3.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbacavir Abacavir may decrease the excretion rate of Sitagliptin which could result in a higher serum level. Abametapir The serum concentration of Sitagliptin can be increased when it is combined with Abametapir. Abatacept The metabolism of Sitagliptin can be increased when combined with Abatacept. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Sitagliptin. Abiraterone The metabolism of Sitagliptin can be decreased when combined with Abiraterone. - Food Interactions
- Take with or without food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Sitagliptin fumarate Not Available 837430-24-7 YRKLLQIZVVYDQY-OIJPFUDISA-N Sitagliptin hydrochloride monohydrate 6DH2XG35TG 862156-92-1 YPULIQLVSSZRST-KLQYNRQASA-N Sitagliptin malate 6Q9M3E3GG7 1240039-02-4 ASAFEPPKGUGNEZ-AMMWVCRBSA-N Sitagliptin phosphate TS63EW8X6F 654671-77-9 GQPYTJVDPQTBQC-KLQYNRQASA-N Sitagliptin tartrate hemihydrate 79C7Y78XGP 862156-93-2 JEMGLDGZRMYQLM-RFGXFKENSA-N - Product Images
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Januvia Tablet, film coated 50 mg Oral Merck Sharp & Dohme B.V. 2016-09-08 Not applicable EU 
Januvia Tablet, film coated 25 mg Oral Merck Sharp & Dohme B.V. 2016-09-08 Not applicable EU Januvia Tablet, film coated 50 mg/1 Oral A-S Medication Solutions 2006-10-16 Not applicable US 
Januvia Tablet, film coated 100 mg Oral Merck Sharp & Dohme B.V. 2016-09-08 Not applicable EU Januvia Tablet, film coated 25 mg/1 Oral Avera McKennan Hospital 2016-10-20 2017-05-24 US - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Ach-sitagliptin Tablet 50 mg Oral Accord Healthcare, S.L.U. 2023-05-12 Not applicable Canada 
Ach-sitagliptin Tablet 25 mg Oral Accord Healthcare, S.L.U. 2023-05-12 Not applicable Canada Ach-sitagliptin Tablet 100 mg Oral Accord Healthcare, S.L.U. 2023-05-12 Not applicable Canada Ag-sitagliptin Tablet 100 mg Oral Angita Pharma Inc. 2023-12-01 Not applicable Canada Ag-sitagliptin Tablet 50 mg Oral Angita Pharma Inc. 2023-12-01 Not applicable Canada - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Apo-sitagliptin Malate / Metformin Hydrochloride Sitagliptin malate (50 mg) + Metformin hydrochloride (500 mg) Tablet Oral Apotex Corporation 2022-11-07 Not applicable Canada Apo-sitagliptin Malate / Metformin Hydrochloride Sitagliptin malate (50 mg) + Metformin hydrochloride (1000 mg) Tablet Oral Apotex Corporation 2022-11-07 Not applicable Canada Apo-sitagliptin Malate / Metformin Hydrochloride Sitagliptin malate (50 mg) + Metformin hydrochloride (850 mg) Tablet Oral Apotex Corporation 2022-11-07 Not applicable Canada Apo-sitagliptin-metformin Sitagliptin phosphate (50 mg) + Metformin hydrochloride (850 mg) Tablet Oral Apotex Corporation Not applicable Not applicable Canada Apo-sitagliptin-metformin Sitagliptin phosphate (50 mg) + Metformin hydrochloride (500 mg) Tablet Oral Apotex Corporation Not applicable Not applicable Canada
Categories
- ATC Codes
- A10BH51 — Sitagliptin and simvastatin
- A10BH — Dipeptidyl peptidase 4 (DPP-4) inhibitors
- A10B — BLOOD GLUCOSE LOWERING DRUGS, EXCL. INSULINS
- A10 — DRUGS USED IN DIABETES
- A — ALIMENTARY TRACT AND METABOLISM
- A10BD — Combinations of oral blood glucose lowering drugs
- A10B — BLOOD GLUCOSE LOWERING DRUGS, EXCL. INSULINS
- A10 — DRUGS USED IN DIABETES
- A — ALIMENTARY TRACT AND METABOLISM
- A10BD — Combinations of oral blood glucose lowering drugs
- A10B — BLOOD GLUCOSE LOWERING DRUGS, EXCL. INSULINS
- A10 — DRUGS USED IN DIABETES
- A — ALIMENTARY TRACT AND METABOLISM
- A10BD — Combinations of oral blood glucose lowering drugs
- A10B — BLOOD GLUCOSE LOWERING DRUGS, EXCL. INSULINS
- A10 — DRUGS USED IN DIABETES
- A — ALIMENTARY TRACT AND METABOLISM
- A10BH — Dipeptidyl peptidase 4 (DPP-4) inhibitors
- A10B — BLOOD GLUCOSE LOWERING DRUGS, EXCL. INSULINS
- A10 — DRUGS USED IN DIABETES
- A — ALIMENTARY TRACT AND METABOLISM
- Drug Categories
- Agents causing angioedema
- Alimentary Tract and Metabolism
- Blood Glucose Lowering Agents
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- DPP-IV Inhibitors
- Drugs that are Mainly Renally Excreted
- Drugs Used in Diabetes
- Enzyme Inhibitors
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Hypoglycemia-Associated Agents
- Incretins
- OAT3/SLC22A8 Substrates
- Oral Hypoglycemics
- P-glycoprotein substrates
- Protease Inhibitors
- Triazoles
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as beta amino acids and derivatives. These are amino acids having a (-NH2) group attached to the beta carbon atom.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- Beta amino acids and derivatives
- Alternative Parents
- Amphetamines and derivatives / Triazolopyrazines / Aralkylamines / Fluorobenzenes / Pyrazines / Aryl fluorides / Triazoles / Tertiary carboxylic acid amides / Heteroaromatic compounds / Azacyclic compounds show 7 more
- Substituents
- 1,2,4-triazole / Alkyl fluoride / Alkyl halide / Amine / Amphetamine or derivatives / Aralkylamine / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle show 25 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- trifluorobenzene, triazolopyrazine (CHEBI:40237)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- QFP0P1DV7Z
- CAS number
- 486460-32-6
- InChI Key
- MFFMDFFZMYYVKS-SECBINFHSA-N
- InChI
- InChI=1S/C16H15F6N5O/c17-10-6-12(19)11(18)4-8(10)3-9(23)5-14(28)26-1-2-27-13(7-26)24-25-15(27)16(20,21)22/h4,6,9H,1-3,5,7,23H2/t9-/m1/s1
- IUPAC Name
- (3R)-3-amino-1-[3-(trifluoromethyl)-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one
- SMILES
- N[C@@H](CC(=O)N1CCN2C(C1)=NN=C2C(F)(F)F)CC1=CC(F)=C(F)C=C1F
References
- Synthesis Reference
Nurit Perlman, Marina Etinger, Valerie Niddam-Hildesheim, Mili Abramov, "Preparation of sitagliptin intermediate." U.S. Patent US20090192326, issued July 30, 2009.
US20090192326- General References
- Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang AQ, Zeng W, Musson D, Winchell G, Davies MJ, Ramael S, Gottesdiener KM, Wagner JA: Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther. 2005 Dec;78(6):675-88. [Article]
- Herman GA, Bergman A, Liu F, Stevens C, Wang AQ, Zeng W, Chen L, Snyder K, Hilliard D, Tanen M, Tanaka W, Meehan AG, Lasseter K, Dilzer S, Blum R, Wagner JA: Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects. J Clin Pharmacol. 2006 Aug;46(8):876-86. [Article]
- Karasik A, Aschner P, Katzeff H, Davies MJ, Stein PP: Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Curr Med Res Opin. 2008 Feb;24(2):489-96. doi: 10.1185/030079908X261069 . [Article]
- Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch C: Emerging role of dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes. Vasc Health Risk Manag. 2008;4(4):753-68. [Article]
- Vincent SH, Reed JR, Bergman AJ, Elmore CS, Zhu B, Xu S, Ebel D, Larson P, Zeng W, Chen L, Dilzer S, Lasseter K, Gottesdiener K, Wagner JA, Herman GA: Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C]sitagliptin in humans. Drug Metab Dispos. 2007 Apr;35(4):533-8. doi: 10.1124/dmd.106.013136. Epub 2007 Jan 12. [Article]
- FDA Drug Approval Package: Sitagliptin [Link]
- Merck Pregnancy Registry: Sitagliptin [Link]
- FDA Approved Drug Products: JANUMET (sitagliptin and metformin hydrochloride) tablets, for oral use [Link]
- FDA Approved Drug Products: JANUVIA (sitagliptin) tablets, for oral use [Link]
- FDA Approved Drug Products: STEGLUJAN (ertugliflozin and sitagliptin) tablets, for oral use [Link]
- FDA Approved Drug Products: JANUVIA (sitagliptin) tablets, for oral use, 2022 [Link]
- External Links
- Human Metabolome Database
- HMDB0015390
- KEGG Drug
- D08516
- PubChem Compound
- 4369359
- PubChem Substance
- 46505822
- ChemSpider
- 3571948
- BindingDB
- 11162
- 593411
- ChEBI
- 40237
- ChEMBL
- CHEMBL1422
- ZINC
- ZINC000001489478
- Therapeutic Targets Database
- DAP000639
- PharmGKB
- PA164748978
- PDBe Ligand
- 715
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Sitagliptin
- PDB Entries
- 1x70 / 4ffw / 7y4g
- FDA label
- Download (405 KB)
- MSDS
- Download (22.3 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Active Not Recruiting Not Available Diabetes 1 somestatus stop reason just information to hide Not Available Active Not Recruiting Other Type 2 Diabetes Mellitus 1 somestatus stop reason just information to hide Not Available Completed Not Available Chronic Kidney Disease (CKD) 1 somestatus stop reason just information to hide Not Available Completed Not Available Diabetes 2 somestatus stop reason just information to hide Not Available Completed Not Available Diabetes / Type 2 Diabetes Mellitus 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- AQ Pharmaceuticals Inc.
- A-S Medication Solutions LLC
- Lake Erie Medical and Surgical Supply
- Merck & Co.
- Murfreesboro Pharmaceutical Nursing Supply
- Physicians Total Care Inc.
- Resource Optimization and Innovation LLC
- Dosage Forms
Form Route Strength Tablet Oral 27.238 mg Tablet Oral 1000.000 mg Tablet Oral 28.345 mg Tablet Oral 54.475 mg Tablet, film coated Oral 128.4 Mg Tablet, film coated Oral 64.2 Mg Tablet Oral 100.000 mg Tablet Oral Tablet, coated Oral 5 mg Tablet, coated Oral 7.5 mg Tablet Oral Tablet, film coated Oral Tablet, extended release Oral Tablet, film coated, extended release Oral Tablet, film coated, extended release Oral 1000 mg Tablet, film coated, extended release Oral 500 mg Tablet, film coated Oral 1000.0 mg Tablet, film coated Oral 500.0 mg Tablet, film coated Oral 850.0 mg Tablet Oral 100 mg Tablet Oral 25 mg Tablet Oral 50 mg Tablet, film coated Oral 100 mg/1 Tablet, film coated Oral 128.5 mg Tablet, film coated Oral 25 mg/1 Tablet, film coated Oral 50 mg/1 Tablet, film coated Oral 64.25 mg Tablet Oral 50.000 mg Tablet, film coated Oral 113.37 Mg Tablet, film coated Oral 56.69 Mg Tablet, coated Oral 25 mg Tablet Oral 850.000 mg Tablet Oral 100 mg/1 Tablet Oral 25 mg/1 Tablet Oral 50 mg/1 Tablet, film coated Oral Tablet, film coated Oral 113374 MG Tablet, film coated Oral 56687 MG Tablet, film coated Oral 50 mg Tablet, film coated Oral 130.47 MG Tablet, film coated Oral 65235 MG Tablet, film coated Tablet, film coated Oral 25 MG Tablet, film coated Oral 50 MG Tablet, film coated Oral 100 mg Tablet, coated Oral Tablet Oral 25.000 mg Tablet, coated Oral 100 mg Tablet, coated Oral 50 mg - Prices
Unit description Cost Unit Januvia 90 25 mg tablet Bottle 686.36USD bottle Januvia 30 100 mg tablet Bottle 228.81USD bottle Januvia 50 mg tablet 7.48USD tablet Januvia 100 mg tablet 7.33USD tablet Januvia 25 mg tablet 7.33USD tablet DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region CA2536251 No 2009-08-04 2024-08-27 Canada CA2450740 No 2006-02-14 2022-07-05 Canada US7326708 Yes 2008-02-05 2027-05-24 US US6699871 Yes 2004-03-02 2023-01-26 US US7125873 Yes 2006-10-24 2023-01-26 US US8414921 Yes 2013-04-09 2029-01-21 US US6340475 No 2002-01-22 2016-09-19 US US6635280 No 2003-10-21 2016-09-19 US US6303661 No 2001-10-16 2017-04-24 US US6890898 No 2005-05-10 2019-02-02 US US7078381 No 2006-07-18 2019-02-02 US US7459428 No 2008-12-02 2019-02-02 US US8168637 No 2012-05-01 2022-06-26 US US8080580 No 2011-12-20 2030-07-13 US US9439901 No 2016-09-13 2030-10-21 US US9308204 No 2016-04-12 2030-10-21 US US10925871 No 2015-02-25 2035-02-25 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source logP 1.5 Not Available - Predicted Properties
Property Value Source Water Solubility 0.034 mg/mL ALOGPS logP 1.95 ALOGPS logP 1.26 Chemaxon logS -4.1 ALOGPS pKa (Strongest Basic) 8.78 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 77.04 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 87.49 m3·mol-1 Chemaxon Polarizability 32.66 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 1.0 Blood Brain Barrier + 0.9438 Caco-2 permeable - 0.6415 P-glycoprotein substrate Substrate 0.6509 P-glycoprotein inhibitor I Inhibitor 0.7141 P-glycoprotein inhibitor II Inhibitor 0.5248 Renal organic cation transporter Inhibitor 0.592 CYP450 2C9 substrate Non-substrate 0.9277 CYP450 2D6 substrate Non-substrate 0.7228 CYP450 3A4 substrate Substrate 0.6412 CYP450 1A2 substrate Non-inhibitor 0.7178 CYP450 2C9 inhibitor Inhibitor 0.6111 CYP450 2D6 inhibitor Non-inhibitor 0.538 CYP450 2C19 inhibitor Inhibitor 0.7048 CYP450 3A4 inhibitor Inhibitor 0.5358 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.8336 Ames test Non AMES toxic 0.5487 Carcinogenicity Non-carcinogens 0.7973 Biodegradation Not ready biodegradable 1.0 Rat acute toxicity 2.8093 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.7076 hERG inhibition (predictor II) Inhibitor 0.6936
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 187.387655 predictedDarkChem Lite v0.1.0 [M-H]- 178.88033 predictedDeepCCS 1.0 (2019) [M+H]+ 188.490855 predictedDarkChem Lite v0.1.0 [M+H]+ 181.2759 predictedDeepCCS 1.0 (2019) [M+Na]+ 187.386255 predictedDarkChem Lite v0.1.0 [M+Na]+ 187.91936 predictedDeepCCS 1.0 (2019)
Targets
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Use our structured and evidence-based datasets to unlock newinsights and accelerate drug research.
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation (PubMed:10900005, PubMed:10951221, PubMed:11772392, PubMed:17287217). Acts as a positive regulator of T-cell coactivation, by binding at least ADA, CAV1, IGF2R, and PTPRC (PubMed:10900005, PubMed:10951221, PubMed:11772392, PubMed:14691230). Its binding to CAV1 and CARD11 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner (PubMed:17287217). Its interaction with ADA also regulates lymphocyte-epithelial cell adhesion (PubMed:11772392). In association with FAP is involved in the pericellular proteolysis of the extracellular matrix (ECM), the migration and invasion of endothelial cells into the ECM (PubMed:10593948, PubMed:16651416). May be involved in the promotion of lymphatic endothelial cells adhesion, migration and tube formation (PubMed:18708048). When overexpressed, enhanced cell proliferation, a process inhibited by GPC3 (PubMed:17549790). Acts also as a serine exopeptidase with a dipeptidyl peptidase activity that regulates various physiological processes by cleaving peptides in the circulation, including many chemokines, mitogenic growth factors, neuropeptides and peptide hormones such as brain natriuretic peptide 32 (PubMed:10570924, PubMed:16254193). Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline (PubMed:10593948)
- Specific Function
- aminopeptidase activity
- Gene Name
- DPP4
- Uniprot ID
- P27487
- Uniprot Name
- Dipeptidyl peptidase 4
- Molecular Weight
- 88277.935 Da
References
- Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang AQ, Zeng W, Musson D, Winchell G, Davies MJ, Ramael S, Gottesdiener KM, Wagner JA: Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther. 2005 Dec;78(6):675-88. [Article]
- Bergman AJ, Stevens C, Zhou Y, Yi B, Laethem M, De Smet M, Snyder K, Hilliard D, Tanaka W, Zeng W, Tanen M, Wang AQ, Chen L, Winchell G, Davies MJ, Ramael S, Wagner JA, Herman GA: Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther. 2006 Jan;28(1):55-72. [Article]
- Gallwitz B: Therapies for the treatment of type 2 diabetes mellitus based on incretin action. Minerva Endocrinol. 2006 Jun;31(2):133-47. [Article]
- Herman GA, Bergman A, Liu F, Stevens C, Wang AQ, Zeng W, Chen L, Snyder K, Hilliard D, Tanen M, Tanaka W, Meehan AG, Lasseter K, Dilzer S, Blum R, Wagner JA: Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects. J Clin Pharmacol. 2006 Aug;46(8):876-86. [Article]
- Miller S, St Onge EL: Sitagliptin: a dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Ann Pharmacother. 2006 Jul-Aug;40(7-8):1336-43. [Article]
- Karasik A, Aschner P, Katzeff H, Davies MJ, Stein PP: Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Curr Med Res Opin. 2008 Feb;24(2):489-96. doi: 10.1185/030079908X261069 . [Article]
- Pratley RE, Salsali A: Inhibition of DPP-4: a new therapeutic approach for the treatment of type 2 diabetes. Curr Med Res Opin. 2007 Apr;23(4):919-31. [Article]
- Lyseng-Williamson KA: Sitagliptin. Drugs. 2007;67(4):587-97. [Article]
- Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P: Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007 Sep;9(5):733-45. Epub 2007 Jun 26. [Article]
- Gallwitz B: Sitagliptin: Profile of a novel DPP-4 inhibitor for the treatment of type 2 diabetes. Drugs Today (Barc). 2007 Jan;43(1):13-25. [Article]
- Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch C: Emerging role of dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes. Vasc Health Risk Manag. 2008;4(4):753-68. [Article]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
- Nadkarni P, Chepurny OG, Holz GG: Regulation of glucose homeostasis by GLP-1. Prog Mol Biol Transl Sci. 2014;121:23-65. doi: 10.1016/B978-0-12-800101-1.00002-8. [Article]
- Gallwitz B: Novel Therapeutic Approaches in Diabetes. Endocr Dev. 2016;31:43-56. doi: 10.1159/000439372. Epub 2016 Jan 19. [Article]
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Scheen AJ: Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes Metab. 2010 Aug;12(8):648-58. doi: 10.1111/j.1463-1326.2010.01212.x. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316)
- Specific Function
- arachidonic acid epoxygenase activity
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- Scheen AJ: Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes Metab. 2010 Aug;12(8):648-58. doi: 10.1111/j.1463-1326.2010.01212.x. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
References
- Scheen AJ: Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes Metab. 2010 Aug;12(8):648-58. doi: 10.1111/j.1463-1326.2010.01212.x. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- Curator comments
- Substrate profile was demonstrated in vitro using human OAT3 expressed on CHO-K1 cells.
- General Function
- Functions as an organic anion/dicarboxylate exchanger that couples organic anion uptake indirectly to the sodium gradient (PubMed:14586168, PubMed:15644426, PubMed:15846473, PubMed:16455804, PubMed:31553721). Transports organic anions such as estrone 3-sulfate (E1S) and urate in exchange for dicarboxylates such as glutarate or ketoglutarate (2-oxoglutarate) (PubMed:14586168, PubMed:15846473, PubMed:15864504, PubMed:22108572, PubMed:23832370). Plays an important role in the excretion of endogenous and exogenous organic anions, especially from the kidney and the brain (PubMed:11306713, PubMed:14586168, PubMed:15846473). E1S transport is pH- and chloride-dependent and may also involve E1S/cGMP exchange (PubMed:26377792). Responsible for the transport of prostaglandin E2 (PGE2) and prostaglandin F2(alpha) (PGF2(alpha)) in the basolateral side of the renal tubule (PubMed:11907186). Involved in the transport of neuroactive tryptophan metabolites kynurenate and xanthurenate (PubMed:22108572, PubMed:23832370). Functions as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4), dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins (PubMed:28534121). May be involved in the basolateral transport of steviol, a metabolite of the popular sugar substitute stevioside (PubMed:15644426). May participate in the detoxification/ renal excretion of drugs and xenobiotics, such as the histamine H(2)-receptor antagonists fexofenadine and cimetidine, the antibiotic benzylpenicillin (PCG), the anionic herbicide 2,4-dichloro-phenoxyacetate (2,4-D), the diagnostic agent p-aminohippurate (PAH), the antiviral acyclovir (ACV), and the mycotoxin ochratoxin (OTA), by transporting these exogenous organic anions across the cell membrane in exchange for dicarboxylates such as 2-oxoglutarate (PubMed:11669456, PubMed:15846473, PubMed:16455804). Contributes to the renal uptake of potent uremic toxins (indoxyl sulfate (IS), indole acetate (IA), hippurate/N-benzoylglycine (HA) and 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF)), pravastatin, PCG, E1S and dehydroepiandrosterone sulfate (DHEAS), and is partly involved in the renal uptake of temocaprilat (an angiotensin-converting enzyme (ACE) inhibitor) (PubMed:14675047). May contribute to the release of cortisol in the adrenals (PubMed:15864504). Involved in one of the detoxification systems on the choroid plexus (CP), removes substrates such as E1S or taurocholate (TC), PCG, 2,4-D and PAH, from the cerebrospinal fluid (CSF) to the blood for eventual excretion in urine and bile (By similarity). Also contributes to the uptake of several other organic compounds such as the prostanoids prostaglandin E(2) and prostaglandin F(2-alpha), L-carnitine, and the therapeutic drugs allopurinol, 6-mercaptopurine (6-MP) and 5-fluorouracil (5-FU) (By similarity). Mediates the transport of PAH, PCG, and the statins pravastatin and pitavastatin, from the cerebrum into the blood circulation across the blood-brain barrier (BBB). In summary, plays a role in the efflux of drugs and xenobiotics, helping reduce their undesired toxicological effects on the body (By similarity)
- Specific Function
- organic anion transmembrane transporter activity
- Gene Name
- SLC22A8
- Uniprot ID
- Q8TCC7
- Uniprot Name
- Organic anion transporter 3
- Molecular Weight
- 59855.585 Da
References
- VanWert AL, Gionfriddo MR, Sweet DH: Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology. Biopharm Drug Dispos. 2010 Jan;31(1):1-71. doi: 10.1002/bdd.693. [Article]
Drug created at May 16, 2007 17:36 / Updated at October 29, 2024 18:22