METABOLISM OF THE CALCIUM-ANTAGONIST, MIBEFRADIL (POSICOR(TM), RO-40-5967) .2. METABOLISM IN HEPATIC MICROSOMES FROM RAT, MARMOSET, CYNOMOLGUS MONKEY, RABBIT AND MAN

1. The calcium antagonist, mibefradil, is converted to some 30 metabol ites after incubation with hepatic microsomes from the rat, marmoset, cynomolgus monkey, rabbit and man. 2. The wide inter-species differenc es in metabolic profile stem mainly from variations in the activity of the microsomal esterase, which hydrolyses the ester side-chain of mib efradil to give the alcohol metabolite, Ro 40-5966. Hydrolysis is espe cially marked in the cynomolgus monkey and rabbit, less in man and lea st in the rat and marmoset. 3. The biotransformation of this alcohol m etabolite by cytochromes P450 is more facile than that of the parent c ompound, leads to fewer metabolites and the metabolic profiles in all species are similar. 4. The most important cytochrome P450-mediated me tabolic process in microsomes in all species is hydroxylation at the b enzylic carbon atom of the tetrahydronaphthyl group; further oxidation of the resultant secondary alcohol to a ketone also occurs. These rea ctions indicate the route of the biosynthetic pathway which leads to t he major, naphthylglucuronide metabolites previously isolated from rat bile. 5. Dealkylation of the tertiary amino group is also important a nd leads to compounds lacking either the N-methyl group or the propylb enzimidazole moiety. 6. Hydroxylation of the benzimidazole ring at bot h the 4- and 5-positions is largely restricted to mibefradil and does not occur to a significant extent with Ro 40-5966.