Influence of sesamin on CYP 2C‐mediated diclofenac metabolism: in vitro and in vivo analysis

Our previous studies revealed that sesamin caused a mechanism‐based inhibition ( MBI ) of CYP 2C9 in human liver microsomes. Additionally, we observed a similar MBI of CYP 2C by sesamin in the rat liver microsomes. Sesamin‐induced difference spectra of rat or human liver microsomes in the presence of NADPH showed a peak at 459 nm, suggesting the formation of a metabolic–intermediate ( MI ) complex of cytochrome P450 and the methylenedioxyphenyl group of sesamin. However, the peak disappeared in both liver microsomes within 30 min after the termination of the metabolism. These results suggest that the MI complex of cytochrome P450 and sesamin is unstable, and the effects of sesamin on human CYP 2C9‐ or rat CYP 2C‐mediated drug metabolism may be small. To confirm this, in vivo studies using rats were performed. The pharmacokinetics of diclofenac, which is mainly metabolized by CYP 2C11 in male rats, were investigated after a 3‐days administration of sesamin (0, 10, and 100 mg/kg bw). No significant differences were observed among the three groups in the pharmacokinetic parameters, C max , T max , and AUC . Furthermore, administration of sesamin to rats for 7 days had no significant effects on diclofenac hydroxylation activity in rat liver microsomes. These results demonstrate that no significant interaction occurs between diclofenac and sesamin in rats. Moreover, the results of these in vitro and in vivo studies suggest that no significant interaction may occur between sesamin and diclofenac when sesamin is administered to humans as a supplement, since the standard sesamin dose in humans is much lower than that administered to rats in this study.