Species-related exposure of phase II metabolite gemfibrozil 1-O-β-glucuronide between human and mice: A net induction of mouse P450 activity was revealed.

Abstract

Gemfibrozil is a fibrate drug used widely for dyslipidemia associated with atherosclerosis. Clinically, both gemfibrozil and its phase II metabolite gemfibrozil 1-O-β-glucuronide (gem-glu) are involved in drug-drug interaction (DDI). But the DDI risk caused by gem-glu between human and mice has not been compared. In this study, six volunteers were recruited and took a therapeutic dose of gemfibrozil for 3 days for examination of the gemfibrozil and gem-glu level in human. Male mice were fed a gemfibrozil diet (0.75%) for 7 days, following which a cocktail-based inhibitory DDI experiment was performed. Plasma samples and liver tissues from mice were collected for determination of gemfibrozil, gem-glu concentration and cytochrome p450 enzyme (P450) induction analysis. In human, the molar ratio of gem-glu/gemfibrozil was 15% and 10% at the trough concentration and the concentration at 1.5 h after the 6th dose. In contrast, this molar ratio at steady state in mice was 91%, demonstrating a 6- to 9-fold difference compared with that in human. Interestingly, a net induction of P450 activity and in vivo inductive DDI potential in mice was revealed. The P450 activity was not inhibited although the gem-glu concentration was high. These data suggested species difference of relative gem-glu exposure between human and mice, as well as a net inductive DDI potential of gemfibrozil in mouse model.

• Authors: Min Luo, Manyun Dai, Hante Lin, Minzhu Xie, Jiao Lin, Aiming Liu, Julin Yang
• Journal: Biopharmaceutics & drug disposition (Biopharm Drug Dispos) Vol. 38 Issue 9 Pg. 535-542 (Dec 2017) ISSN: 1099-081X [Electronic] England
• PMID: 28946176 (Publication Type: Clinical Trial, Journal Article)
• Copyright: Copyright © 2017 John Wiley & Sons, Ltd.

Chemical References

• Cytochrome P-450 Enzyme Inducers
• Glucuronates
• Hypolipidemic Agents
• Cytochrome P-450 Enzyme System
• gemfibrozil 1-O-acylglucuronide
• Gemfibrozil

Topics

• Adult
• Animals
• Cytochrome P-450 Enzyme Inducers (administration & dosage, pharmacokinetics, pharmacology)
• Cytochrome P-450 Enzyme System (drug effects, metabolism)
• Drug Interactions
• Gemfibrozil (analogs & derivatives, pharmacokinetics, pharmacology)
• Glucuronates (pharmacokinetics, pharmacology)
• Humans
• Hypolipidemic Agents (administration & dosage, pharmacokinetics, pharmacology)
• Liver (metabolism)
• Male
• Mice
• Species Specificity
• Time Factors
• Young Adult