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

Abstract

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.

• Authors: Hyeon-Uk Jeong, Ju-Hyun Kim, Dae Young Lee, Hyun Joo Shim, Hye Suk Lee
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 20 Issue 12 Pg. 21802-15 (Dec 04 2015) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 26690104 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(3-amino-4-(2,4,5-trifluorophenyl)butanoyl)-3-(tert-butoxymethyl)piperazin-2-one
• Hypoglycemic Agents
• Piperazines
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human

Topics

• Cells, Cultured
• Cytochrome P-450 CYP3A (metabolism)
• Diabetes Mellitus, Type 2 (drug therapy)
• Drug Evaluation, Preclinical
• Hepatocytes (enzymology)
• Humans
• Hypoglycemic Agents (metabolism)
• Inactivation, Metabolic
• Kinetics
• Liver (cytology, enzymology)
• Microsomes, Liver (enzymology)
• Piperazines (metabolism)