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.

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.

Adrenoceptors mediating relaxation to catecholamines in rat isolated jejunum.

1. The characteristics of adrenoceptors mediating relaxation to catecholamines in rat isolated jejunum were investigated. 2. Catecholamines and BRL 37344 produced relaxation of the KCl-contracted strips with an order of potency of isoprenaline (1.0) > BRL 37344 (0.63) > noradrenaline (0.1) > adrenaline (0.04). 3. In the presence of both prazosin (1 microM) and propranolol (1 microM) only small dextral shifts of the concentration-response curves to agonists were observed and an order of potency of BRL 37344 (2.5) > isoprenaline (1.0) > noradrenaline (0.2) > adrenaline (0.1) was obtained. 4. In the presence of prazosin (1 microM) and propranolol (1 microM), cyanopindolol (0.1-10 microM) produced a concentration-dependent rightward shift of the concentration-response curve to adrenaline with a Schild slope not significantly different from unity and a mean pA2 value of 7.01. 5. The resistance of relaxant responses to propranolol, the relatively high potency of BRL 37344 compared to catecholamines and the competitive antagonism of relaxant responses to adrenaline by cyanopindolol suggest that beta-adrenoceptors in rat small intestine are mainly atypical in nature.