Vol. 30, Issue 8, 904-910, August 2002

Sex Difference in Inhibition of In Vitro Mexazolam Metabolism by Various 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors in Rat Liver Microsomes

Michi Ishigami, Wataru Takasaki, Toshihiko Ikeda, Toru Komai, Kiyomi Ito, and Yuichi Sugiyama

Drug Metabolism and Pharmacokinetics Research Laboratories, New Drug Development Division and Product Strategy Department, Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan (M.I., W.T., T.I., T.K.); School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo, Japan (K.I.); and Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan (Y.S.)

To identify an appropriate animal model for the study of drug interaction via CYP3A4 inhibition, the inhibition of in vitro mexazolam metabolism by various 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors [simvastatin (lactone), simvastatin acid, fluvastatin, atorvastatin, cerivastatin, pravastatin lactone, and pravastatin (acid)] in male and female rat liver microsomes was investigated and compared with that by HMG-CoA reductase inhibitors in human liver microsomes reported previously. The metabolism of mexazolam in male and female rat liver microsomes was inhibited by all the HMG-CoA reductase inhibitors examined except pravastatin (acid). The K_i values in female rats were lower than those in male rats, demonstrating the presence of a sex difference in the inhibition potency of HMG-CoA reductase inhibitors toward mexazolam. Using anti-cytochrome P450 (P450) antisera, the main P450 isozyme responsible for the metabolism of mexazolam was identified as CYP3A in female rats and CYP2C11 in male rats. Based on these results, we speculate that the sex difference in the inhibition potency of HMG-CoA reductase inhibitors for mexazolam observed in rats is caused by their different inhibition potencies against CYP2C11 and CYP3A isoforms. For mexazolam metabolism, the results obtained in female rats, rather than those in male rats, seem to be a much better reflection of the results in humans. Since species and sex differences were observed in P450 isozymes in the present study, our results show that establishing appropriate experimental conditions, in particular with respect to the P450 isozymes responsible for the drug metabolism in question, is indispensable for the investigation of drug interactions using rats as a model animal for humans.