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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.

Authors :
Luo, Min
Dai, Manyun
Lin, Hante
Xie, Minzhu
Lin, Jiao
Liu, Aiming
Yang, Julin
Source :
Biopharmaceutics & Drug Disposition; Dec2017, Vol. 38 Issue 9, p535-542, 8p
Publication Year :
2017

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
01422782
Volume :
38
Issue :
9
Database :
Complementary Index
Journal :
Biopharmaceutics & Drug Disposition
Publication Type :
Academic Journal
Accession number :
126565300
Full Text :
https://doi.org/10.1002/bdd.2105