The involvement of flavin-containing monooxygenase but not CYP3A4 in metabolism of itopride hydrochloride, a gastroprokinetic agent: Comparison with cisapride and mosapride citrate

The goals of the present study were to identify the enzyme responsible for metabolism of itopride hydrochloride (itopride) and to evaluate the likelih ood of drug interaction involving itopride. In human liver microsomes, the involvement of flavin-containing monooxygenase in N-oxygenation, the major metabolic pathway of itopride, was indicated by the following results: inhi bition by methimazole and thiourea, heat inactivation, and protection again st heat inactivation by NADPH. When the effects of ketoconazole on the meta bolism of itopride, cisapride, and mosapride citrate (mosapride) were exami ned using human liver microsomes, ketoconazole strongly inhibited the forma tion of the primary metabolites of cisapride and mosapride, but not itoprid e. Other cytochrome P450 (CYP) 3A4 inhibitors, cimetidine, erythromycin, an d clarithromycin, also inhibited the metabolism of cisapride and mosapride. In an in vivo study, itopride (30 mg/kg), cisapride (1.5 mg/kg), or mosapr ide (3 mg/kg) was orally administered to male rats with or without oral pre treatment with ketoconazole (120 mg/kg) twice daily for 2 days. The ketocon azole pretreatment significantly increased the area under the serum concent ration curve and the maximum serum concentration of cisapride and mosapride but had no significant effect on the pharmacokinetics of itopride. In addi tion, itopride did not inhibit five specific CYP-mediated reactions of huma n liver microsomes. These results suggest that itopride is unlikely to alte r the pharmacokinetics of other concomitantly administered drugs.