Metabolism of the calcium antagonist, mibefradil (POSICOR, Ro 40-5967). Part II. Metabolism in hepatic microsomes from rat, marmoset, cynomolgus monkey, rabbit and man.

1. The calcium antagonist, mibefradil, is converted to some 30 metabolites after incubation with hepatic microsomes from the rat, marmoset, cynomolgus monkey, rabbit and man. 2. The wide inter-species differences in metabolic profile stem mainly from variations in the activity of the microsomal esterase, which hydrolyses the ester side-chain of mibefradil to give the alcohol metabolite, Ro 40-5966. Hydrolysis is especially marked in the cynomolgus monkey and rabbit, less in man and least in the rat and marmoset. 3. The biotransformation of this alcohol metabolite by cytochromes P450 is more facile than that of the parent compound, leads to fewer metabolites and the metabolic profiles in all species are similar. 4. The most important cytochrome P450-mediated metabolic process in microsomes in all species is hydroxylation at the benzylic carbon atom of the tetrahydronaphthyl group; further oxidation of the resultant secondary alcohol to a ketone also occurs. These reactions indicate the route of the biosynthetic pathway which leads to the major, naphthyl-glucuronide metabolites previously isolated from rat bile. 5. Dealkylation of the tertiary amino group is also important and leads to compounds lacking either the N-methyl group or the propylbenzimidazole moiety. 6. Hydroxylation of the benzimidazole ring at both the 4- and 5-positions is largely restricted to mibefradil and does not occur to a significant extent with Ro 40-5966.