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. (20th November 2017)

• Record Type: Journal Article
• Authors: Luo, Min; Dai, Manyun; Lin, Hante; Xie, Minzhu; Lin, Jiao; Liu, Aiming; Yang, Julin
• Is Part Of: Biopharmaceutics & drug disposition. Volume 38:Number 9(2017:Dec.)
• Page Start: 535
• Page End: 542
• Publication Date: 2017-11-20
• Subjects: drug–drug interactions -- gemfibrozil -- glucuronidation -- species difference; Biopharmaceutics -- Periodicals; Drugs -- Metabolism -- Periodicals; Pharmacology -- Periodicals; Biopharmaceutics -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; 615.19
• DOI: 10.1002/bdd.2105
• Languages: English
• ISSNs: 0142-2782

Abstract

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.