Metabolism of the calcium antagonist, mibefradil (POSICOR, Ro 40-5967). Part III. Comparative pharmacokinetics of mibefradil and its major metabolites in rat, marmoset, cynomolgus monkey and man.

1. The metabolism of mibefradil has been examined in rat, marmoset, cynomolgus monkey and man after single and multiple oral administration. 2. Metabolites typically represent between 50 and 80% of the circulating drug-related material after single oral doses of mibefradil to man, rat and marmoset. They arise by a combination of enzymatic processes: cytochrome P450-mediated oxidation at saturated and unsaturated carbon atoms, cytochrome P450-catalysed dealkylation and hydrolysis of the ester side-chain. 3. Plasma levels of mibefradil in the cynomolgus monkey are extremely low as a result of very efficient first-pass hydrolysis of its side-chain to give the corresponding alcohol. Steady-state concentrations of this metabolite are comparable with those of the parent drug in man and marmoset, but are relatively low in rat plasma. 4. Hydroxylation at the benzylic carbon of the tetrahydronaphthyl ring leads to further important metabolites in primates, whereas the products of O- and N-demethylation are found in small amounts in all four species. 5. Estimates of the exposure of the various species to the principal metabolites indicate that the choice of the rat, marmoset and cynomolgus monkey for the toxicological assessment of mibefradil was appropriate.