Sex difference in inhibition of in vitro mexazolam metabolism by various 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors in rat liver microsomes.
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.
Drug Metabolism Laboratory, New Drug Development Division and Product Strategy Department, Sankyo Co., Ltd., Shinagawa-ku, Tokyo, Japan.
Michi
M
Ishigami
Wataru
W
Takasaki
Toshihiko
T
Ikeda
Toru
T
Komai
Kiyomi
K
Ito
Yuichi
Y
Sugiyama
D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism*; D001569:Benzodiazepines; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003907:Dexamethasone / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D066298:In Vitro Techniques; D017964:Itraconazole / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors
D014151:Anti-Anxiety Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D001569:Benzodiazepines; D017964:Itraconazole; D003907:Dexamethasone; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C014262:mexazolam