title: Absorption, metabolism, and excretion of [14C]vildagliptin, a novel dipeptidyl peptidase 4 inhibitor, in humans.
abstract: The absorption, metabolism, and excretion of (1-[[3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine (vildagliptin), an orally active and highly selective dipeptidyl peptidase 4 inhibitor developed for the treatment of type 2 diabetes, were evaluated in four healthy male subjects after a single p.o. 100-mg dose of [(14)C]vildagliptin. Serial blood and complete urine and feces were collected for 168 h postdose. Vildagliptin was rapidly absorbed, and peak plasma concentrations were attained at 1.1 h postdose. The fraction of drug absorbed was calculated to be at least 85.4%. Unchanged drug and a carboxylic acid metabolite (M20.7) were the major circulating components in plasma, accounting for 25.7% (vildagliptin) and 55% (M20.7) of total plasma radioactivity area under the curve. The terminal half-life of vildagliptin was 2.8 h. Complete recovery of the dose was achieved within 7 days, with 85.4% recovered in urine (22.6% unchanged drug) and the remainder in feces (4.54% unchanged drug). Vildagliptin was extensively metabolized via at least four pathways before excretion, with the major metabolite M20.7 resulting from cyano group hydrolysis, which is not mediated by cytochrome P450 (P450) enzymes. Minor metabolites resulted from amide bond hydrolysis (M15.3), glucuronidation (M20.2), or oxidation on the pyrrolidine moiety of vildagliptin (M20.9 and M21.6). The diverse metabolic pathways combined with a lack of significant P450 metabolism (1.6% of the dose) make vildagliptin less susceptible to potential pharmacokinetic interactions with comedications of P450 inhibitors/inducers. Furthermore, as vildagliptin is not a P450 inhibitor, it is unlikely that vildagliptin would affect the metabolic clearance of comedications metabolized by P450 enzymes.
authors.affiliation: Department of Drug Metabolism, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, USA. handan.he@novartis.com
authors.forename: Handan
authors.initials: H
authors.lastname: He
authors.forename: Phi
authors.initials: P
authors.lastname: Tran
authors.forename: Hequn
authors.initials: H
authors.lastname: Yin
authors.forename: Harold
authors.initials: H
authors.lastname: Smith
authors.forename: Yannick
authors.initials: Y
authors.lastname: Batard
authors.forename: Lai
authors.initials: L
authors.lastname: Wang
authors.forename: Heidi
authors.initials: H
authors.lastname: Einolf
authors.forename: Helen
authors.initials: H
authors.lastname: Gu
authors.forename: James B
authors.initials: JB
authors.lastname: Mangold
authors.forename: Volker
authors.initials: V
authors.lastname: Fischer
authors.forename: Dan
authors.initials: D
authors.lastname: Howard
mesh_terms: D000042:Absorption; D000218:Adamantane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D019540:Area Under Curve; D002250:Carbon Radioisotopes / Q000378:metabolism / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006801:Humans; D006868:Hydrolysis; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D009570:Nitriles / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding; D011759:Pyrrolidines / Q000378:metabolism / Q000493:pharmacokinetics*; D000077597:Vildagliptin
chemical_list: D002250:Carbon Radioisotopes; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D009570:Nitriles; D011759:Pyrrolidines; D000077597:Vildagliptin; D000218:Adamantane