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Molecules 2015, 20(12), 21802-21815;

In Vitro Metabolic Pathways of the New Anti-Diabetic Drug Evogliptin in Human Liver Preparations

Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Korea
Research Center, Dong-A ST Co., Yongin 446-905, Korea
Author to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 3 November 2015 / Revised: 19 November 2015 / Accepted: 25 November 2015 / Published: 4 December 2015
(This article belongs to the Section Metabolites)
Full-Text   |   PDF [1434 KB, uploaded 4 December 2015]   |  


Evogliptin ((R)-4-((R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl)-piperazin-2-one), is a new dipeptidyl peptidase IV inhibitor used for the treatment of type II diabetes mellitus. The in vitro metabolic pathways of evogliptin were identified in human hepatocytes, liver microsomes, and liver S9 fractions using liquid chromatography-Orbitrap mass spectrometry (LC-HRMS). Five metabolites of evogliptin-4-oxoevogliptin (M1), 4(S)-hydroxyevogliptin (M2), 4(R)-hydroxyevogliptin (M3), 4(S)-hydroxyevogliptin glucuronide (M4), and evogliptin N-sulfate (M5)—were identified in human liver preparations by comparison with authentic standards. We characterized the cytochrome P450 (CYP) enzymes responsible for evogliptin hydroxylation to 4(S)-hydroxyevogliptin (M2) and 4(R)-hydroxyevogliptin (M3) and the UGT enzymes responsible for glucuronidation of 4(S)-hydroxyevogliptin (M2) to 4(S)-hydroxy-evogliptin glucuronide (M4). CYP3A4/5 played the major role in the hydroxylation of evogliptin to 4(S)-hydroxyevogliptin (M2) and 4(R)-hydroxyevogliptin (M3). Glucuronidation of 4(S)-hydroxy-evogliptin (M2) to 4(S)-hydroxyevogliptin glucuronide (M4) was catalyzed by the enzymes UGT2B4 and UGT2B7. These results suggest that the interindividual variability in the metabolism of evogliptin in humans is a result of the genetic polymorphism of the CYP and UGT enzymes responsible for evogliptin metabolism. View Full-Text
Keywords: evogliptin metabolism; human hepatocytes; cytochrome P450; UDP-glucuronosyl- transferases evogliptin metabolism; human hepatocytes; cytochrome P450; UDP-glucuronosyl- transferases

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Jeong, H.-U.; Kim, J.-H.; Lee, D.Y.; Shim, H.J.; Lee, H.S. In Vitro Metabolic Pathways of the New Anti-Diabetic Drug Evogliptin in Human Liver Preparations. Molecules 2015, 20, 21802-21815.

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