Drug interaction between simvastatin and itraconazole in male and female rats

Taking into account the species and sex differences in drug: interactions b ased on the inhibition of cytochrome P450 (P450)mediated drug metabolism, w e examined whether the interaction between simvastatin and itraconazole obs erved in humans could also occur in rats, the most commonly used animal spe cies for pharmacokinetic studies, Itraconazole inhibited the in vitro metab olism of simvastatin in female rat liver microsomes, but not in male rat li ver microsomes. Using anti-P450 antisera, the main P450 isozyme responsible for the metabolism of simvastatin was identified as CYP3A in female rats a nd CYP2C11 in male rats. Therefore, the sex difference in the inhibition of simvastatin metabolism by itraconazole seems to be caused by a difference in the P450 isozymes responsible for the metabolism of simvastatin in male and female rats and the different ability of itraconazole to inhibit CYP3A and. CYP2C11. In addition, the effect of itraconazole on the pharmacokineti cs of simvastatin in rats was also investigated. The area under the curve v alue of simvastatin was increased approximately 1.6-fold by the concomitant use of itraconazole (50 mg/kg) in female rats, whereas in male rats, itrac onazole had no effect. In conclusion, it was found that the results obtaine d in male rats did not reflect the results in humans as far as the inhibiti on of simvastatin metabolism by itraconazole was concerned. The P450 isozym es involved in the metabolism of drugs should be taken into consideration w hen rats are used as a model animal for humans in the investigation of drug interactions.