Drug interaction between cyproheptadine and tipepidine. Effect of single and repeated administrations.

In order to elucidate the interaction between cyproheptadine (CPH) and tipepidine (TP), the disposition of CPH and its metabolites from plasma and the hepatic drug metabolizing enzyme activities in rats dosed singly or repeatedly were investigated. The elimination of CPH and its metabolites, desmethylCPH (DMCPH) and DMCPH-epoxide (DMCPHEPO), from plasma after a single intravenous (i.v.) administration of both CPH and TP was not significantly altered compared with that after CPH alone, although the i.v. administration of DMCPH and TP enhanced the plasma levels of DMCPHEPO. The elimination of TP from plasma was not affected by the coadministration with CPH. The single oral administration of both CPH and TP (50 mg/kg) significantly enhanced the plasma levels of CPH and DMCPH compared with those after CPH alone, consequently resulting in their delayed elimination. However, the coadministration with TP at a low dose (5 mg/kg) hardly affected the plasma decay of CPH and its metabolites. The repeated dosing of them for 7 d obscured the interactive effect. The hepatic drug-metabolizing enzyme activities, cytochrome P-450 and aminopyrine demethylase activity, were greatly increased after the repeated administration of CPH, especially showing much more increased activities after the coadministration with TP. These results suggest that the competition of hepatic oxidative metabolism between CPH or its metabolites and TP based on the depletion of the enzymes might largely be involved in the drug interaction on a single dosing of them and that the repeated dosing of them would dissolve the depletion due to their strongly inductive effect.