Sitagliptin

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
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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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used as adjunct in combination to manageType 2 diabetes mellitusCombination Product in combination with: Ertugliflozin (DB11827)•••••••••••••••••
Used as adjunct in combination to manageType 2 diabetes mellitusCombination Product in combination with: Metformin (DB00331)•••••••••••••••••
Adjunct therapy in management ofType 2 diabetes mellitus•••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

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.

TargetActionsOrganism
ADipeptidyl peptidase 4
inhibitor
Humans
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

198LLabel,4.

Protein binding

38%Label,4.

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.

Hover over products below to view reaction partners

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

350mL/minLabel,2.

Adverse Effects
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Toxicity

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.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Sitagliptin which could result in a higher serum level.
AbametapirThe serum concentration of Sitagliptin can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Sitagliptin can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Sitagliptin.
AbirateroneThe metabolism of Sitagliptin can be decreased when combined with Abiraterone.
Food Interactions
  • Take with or without food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Sitagliptin fumarateNot Available837430-24-7YRKLLQIZVVYDQY-OIJPFUDISA-N
Sitagliptin hydrochloride monohydrate6DH2XG35TG862156-92-1YPULIQLVSSZRST-KLQYNRQASA-N
Sitagliptin malate6Q9M3E3GG71240039-02-4ASAFEPPKGUGNEZ-AMMWVCRBSA-N
Sitagliptin phosphateTS63EW8X6F654671-77-9GQPYTJVDPQTBQC-KLQYNRQASA-N
Sitagliptin tartrate hemihydrate79C7Y78XGP862156-93-2JEMGLDGZRMYQLM-RFGXFKENSA-N
Product Images
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
JanuviaTablet100 mgOralMerck Ltd.2008-01-02Not applicableCanada flag
JanuviaTablet, film coated50 mg/1OralA-S Medication Solutions2006-10-16Not applicableUS flag
JanuviaTablet, film coated50 mgOralMerck Sharp & Dohme B.V.2016-09-08Not applicableEU flag
JanuviaTablet, film coated100 mgOralMerck Sharp & Dohme B.V.2016-09-08Not applicableEU flag
JanuviaTablet, film coated50 mg/1OralA-S Medication Solutions2006-10-16Not applicableUS flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Ach-sitagliptinTablet25 mgOralAccord Healthcare, S.L.U.2023-05-12Not applicableCanada flag
Ach-sitagliptinTablet100 mgOralAccord Healthcare, S.L.U.2023-05-12Not applicableCanada flag
Ach-sitagliptinTablet50 mgOralAccord Healthcare, S.L.U.2023-05-12Not applicableCanada flag
Ag-sitagliptinTablet25 mgOralAngita Pharma Inc.2023-12-01Not applicableCanada flag
Ag-sitagliptinTablet100 mgOralAngita Pharma Inc.2023-12-01Not applicableCanada flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Apo-sitagliptin Malate / Metformin HydrochlorideSitagliptin malate (50 mg) + Metformin hydrochloride (850 mg)TabletOralApotex Corporation2022-11-07Not applicableCanada flag
Apo-sitagliptin Malate / Metformin HydrochlorideSitagliptin malate (50 mg) + Metformin hydrochloride (500 mg)TabletOralApotex Corporation2022-11-07Not applicableCanada flag
Apo-sitagliptin Malate / Metformin HydrochlorideSitagliptin malate (50 mg) + Metformin hydrochloride (1000 mg)TabletOralApotex Corporation2022-11-07Not applicableCanada flag
Apo-sitagliptin-metforminSitagliptin phosphate (50 mg) + Metformin hydrochloride (1000 mg)TabletOralApotex CorporationNot applicableNot applicableCanada flag
Apo-sitagliptin-metforminSitagliptin phosphate (50 mg) + Metformin hydrochloride (850 mg)TabletOralApotex CorporationNot applicableNot applicableCanada flag

Categories

ATC Codes
A10BH51 — Sitagliptin and simvastatinA10BD24 — Sitagliptin and ertugliflozinA10BD07 — Metformin and sitagliptinA10BD29 — Sitagliptin and dapagliflozinA10BH01 — SitagliptinA10BD12 — Pioglitazone and sitagliptin
Drug Categories
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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. FDA Drug Approval Package: Sitagliptin [Link]
  7. Merck Pregnancy Registry: Sitagliptin [Link]
  8. FDA Approved Drug Products: JANUMET (sitagliptin and metformin hydrochloride) tablets, for oral use [Link]
  9. FDA Approved Drug Products: JANUVIA (sitagliptin) tablets, for oral use [Link]
  10. FDA Approved Drug Products: STEGLUJAN (ertugliflozin and sitagliptin) tablets, for oral use [Link]
  11. FDA Approved Drug Products: JANUVIA (sitagliptin) tablets, for oral use, 2022 [Link]
Human Metabolome Database
HMDB0015390
KEGG Drug
D08516
PubChem Compound
4369359
PubChem Substance
46505822
ChemSpider
3571948
BindingDB
11162
RxNav
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
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Not AvailableActive Not RecruitingNot AvailableDiabetes1somestatusstop reasonjust information to hide
Not AvailableActive Not RecruitingOtherType 2 Diabetes Mellitus1somestatusstop reasonjust information to hide
Not AvailableCompletedNot AvailableChronic Kidney Disease (CKD)1somestatusstop reasonjust information to hide
Not AvailableCompletedNot AvailableDiabetes2somestatusstop reasonjust information to hide
Not AvailableCompletedNot AvailableDiabetes / Type 2 Diabetes Mellitus1somestatusstop reasonjust 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
FormRouteStrength
TabletOral27.238 mg
TabletOral1000.000 mg
TabletOral28.345 mg
TabletOral54.475 mg
Tablet, film coatedOral128.4 Mg
Tablet, film coatedOral64.2 Mg
TabletOral100.000 mg
TabletOral
Tablet, coatedOral5 mg
Tablet, coatedOral7.5 mg
TabletOral
Tablet, film coatedOral
Tablet, extended releaseOral
Tablet, film coated, extended releaseOral
Tablet, film coated, extended releaseOral1000 mg
Tablet, film coated, extended releaseOral500 mg
Tablet, film coatedOral1000.0 mg
Tablet, film coatedOral500.0 mg
Tablet, film coatedOral850.0 mg
TabletOral100 mg
TabletOral25 mg
TabletOral50 mg
Tablet, film coatedOral100 mg/1
Tablet, film coatedOral128.5 mg
Tablet, film coatedOral25 mg/1
Tablet, film coatedOral50 mg/1
Tablet, film coatedOral64.25 mg
TabletOral50.000 mg
Tablet, film coatedOral113.37 Mg
Tablet, film coatedOral56.69 Mg
Tablet, coatedOral25 mg
TabletOral850.000 mg
TabletOral100 mg/1
TabletOral25 mg/1
TabletOral50 mg/1
Tablet, film coatedOral
Tablet, film coatedOral113374 MG
Tablet, film coatedOral56687 MG
Tablet, film coatedOral50 mg
Tablet, film coatedOral130.47 MG
Tablet, film coatedOral65235 MG
Tablet, film coated
Tablet, film coatedOral25 MG
Tablet, film coatedOral50 MG
Tablet, film coatedOral100 mg
Tablet, coatedOral
TabletOral25.000 mg
Tablet, coatedOral100 mg
Tablet, coatedOral50 mg
Prices
Unit descriptionCostUnit
Januvia 90 25 mg tablet Bottle686.36USD bottle
Januvia 30 100 mg tablet Bottle228.81USD bottle
Januvia 50 mg tablet7.48USD tablet
Januvia 100 mg tablet7.33USD tablet
Januvia 25 mg tablet7.33USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
CA2536251No2009-08-042024-08-27Canada flag
CA2450740No2006-02-142022-07-05Canada flag
US7326708Yes2008-02-052027-05-24US flag
US6699871Yes2004-03-022023-01-26US flag
US7125873Yes2006-10-242023-01-26US flag
US8414921Yes2013-04-092029-01-21US flag
US6340475No2002-01-222016-09-19US flag
US6635280No2003-10-212016-09-19US flag
US6303661No2001-10-162017-04-24US flag
US6890898No2005-05-102019-02-02US flag
US7078381No2006-07-182019-02-02US flag
US7459428No2008-12-022019-02-02US flag
US8168637No2012-05-012022-06-26US flag
US8080580No2011-12-202030-07-13US flag
US9439901No2016-09-132030-10-21US flag
US9308204No2016-04-122030-10-21US flag
US10925871No2015-02-252035-02-25US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP1.5Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.034 mg/mLALOGPS
logP1.95ALOGPS
logP1.26Chemaxon
logS-4.1ALOGPS
pKa (Strongest Basic)8.78Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area77.04 Å2Chemaxon
Rotatable Bond Count5Chemaxon
Refractivity87.49 m3·mol-1Chemaxon
Polarizability32.66 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9438
Caco-2 permeable-0.6415
P-glycoprotein substrateSubstrate0.6509
P-glycoprotein inhibitor IInhibitor0.7141
P-glycoprotein inhibitor IIInhibitor0.5248
Renal organic cation transporterInhibitor0.592
CYP450 2C9 substrateNon-substrate0.9277
CYP450 2D6 substrateNon-substrate0.7228
CYP450 3A4 substrateSubstrate0.6412
CYP450 1A2 substrateNon-inhibitor0.7178
CYP450 2C9 inhibitorInhibitor0.6111
CYP450 2D6 inhibitorNon-inhibitor0.538
CYP450 2C19 inhibitorInhibitor0.7048
CYP450 3A4 inhibitorInhibitor0.5358
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8336
Ames testNon AMES toxic0.5487
CarcinogenicityNon-carcinogens0.7973
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.8093 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7076
hERG inhibition (predictor II)Inhibitor0.6936
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0295-2921000000-ee26b46d46fd47d93f77
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0a4i-0000900000-ce9211ae5927c697618c
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-052r-0690500000-c28779e719a0e517d106
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0076-0930000000-1337dd7fb10ab92722b5
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-00dl-0900000000-91485eb0052ad2f3637a
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-00di-0900000000-7d92431093315efaed86
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-000i-0390000000-c8853d370b51f01b194b
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-0000900000-2895dd4a879799635ae6
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-007c-0970100000-17431cd80097dff5c35f
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-00dl-0910000000-29041ebd42cb7f6026df
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-00di-0900000000-dc60c3b1e5f0ba0e5e23
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0umi-0900000000-b1e1f886377c8d9b2a5d
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-004i-0900000000-d9e2b332d0ff3c6e283b
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-0000900000-3403c0e74f19a7d0832a
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-007c-0970000000-6aa1fc14d171d0102a2c
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-00dl-0910000000-62ba59074d19e0d89306
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-00di-0900000000-91600010aa7e80c0e67c
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0fmi-0900000000-d38f8b74df088a3b8232
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-004i-0900000000-08cf9f4ac284f2cd9057
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-000i-0390000000-b6e5cd73f4ff7abd2747
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-0000900000-2d6387a099709c33f115
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4r-0005900000-f4e29163927f21d838ba
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-0635900000-91b475056974e92d12ae
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4i-0749600000-cd70ed62c673b33ee005
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-052f-0934000000-9e13cd8e91573f42660b
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-01ot-0941000000-476b2b6f2a0bb8cb8768
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-187.387655
predicted
DarkChem Lite v0.1.0
[M-H]-178.88033
predicted
DeepCCS 1.0 (2019)
[M+H]+188.490855
predicted
DarkChem Lite v0.1.0
[M+H]+181.2759
predicted
DeepCCS 1.0 (2019)
[M+Na]+187.386255
predicted
DarkChem Lite v0.1.0
[M+Na]+187.91936
predicted
DeepCCS 1.0 (2019)

Targets

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Details
1. Dipeptidyl peptidase 4
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
  1. 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]
  2. 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]
  3. Gallwitz B: Therapies for the treatment of type 2 diabetes mellitus based on incretin action. Minerva Endocrinol. 2006 Jun;31(2):133-47. [Article]
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. Lyseng-Williamson KA: Sitagliptin. Drugs. 2007;67(4):587-97. [Article]
  9. 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]
  10. 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]
  11. 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]
  12. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  13. 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]
  14. Gallwitz B: Novel Therapeutic Approaches in Diabetes. Endocr Dev. 2016;31:43-56. doi: 10.1159/000439372. Epub 2016 Jan 19. [Article]
  15. 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
  1. 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
  1. 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
  1. 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
  1. 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 21, 2024 12:56