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

Abstract

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.

The Mibefradil Derivative NNC55-0396, a Specific T-Type Calcium Channel Antagonist, Exhibits Less CYP3A4 Inhibition than Mibefradil

“…The IC 50 and K i of NNC55-0396 are 19-fold higher than that of mibefradil. The higher IC 50 and K i values observed for CYP3A4 in human liver microsomes compared with the values for recombinant CYP3A4 may result from the presence of other microsomal proteins that bind to the inhibitors, or to the presence of other enzymes that can metabolize the inhibitors, thus making them less available to inhibit the targeted enzyme (Wiltshire et al, 1997a). Moreover, the difference could have been contributed by different substrates being used.…”

“…It has been shown that these P450s participate in the metabolism of approximately 80% of therapeutic drugs (Wienkers and Heath, 2005). To obtain a preliminary look at the P450 inhibitory profiles for mibefradil and NNC55-0396, two concentrations of the inhibitors were chosen, 100 nM and 10 M. These two concentrations represent the low and the high concentrations and cover the range of therapeutic plasma concentrations of the inhibitors because it has been reported that the human therapeutic plasma concentration of mibefradil ranges from 300 to 1000 ng/ml after doses of 50 to 100 mg/day, which correspond to 0.5 to 1.8 M mibefradil (Wiltshire et al, 1997a;Welker and Banken, 1998). At 100 nM, mibefradil exhibited more than a 2-fold greater inhibition than NNC55-0396 for CYP3A4 (63 and 27%, respectively, p Ͻ 0.001) (Fig.…”

“…According to Wiltshire et al (1992Wiltshire et al ( , 1997a, 20 to 32% of mibefradil is converted to Ro 40-5966 after clinical administration. Although it has been shown here and by others that mibefradil inhibits several P450s, it has not previously been investigated whether Ro 40-5966 can also inhibit P450s.…”

“…Mibefradil is hydrolyzed by esterase and CYP3A4 to generate a hydroxyl mibefradil, Ro 40-5966 (Wiltshire et al, 1997a), one of many mibefradil metabolites shown to contribute to the L-type Ca 2ϩ channel nonspecific inhibition of mibefradil (Wu et al, 2000). Our results show that Ro 40-5966 inhibits CYP3A4 with an efficacy comparable with mibefradil and thus is 10 times more inhibitory than NNC55-0396.…”

Evaluation system for arrhythmogenic potential of drugs using human-induced pluripotent stem cell-derived cardiomyocytes and gene expression analysis

“…In addition, cell toxicity was apparent when hiPS-CMs were treated with the drugs for > 24 hr at the concentrations described below (data not shown). For (Bachmann et al, 1997), mibefradil (Wiltshire et al, 1997), and terodiline (Hartigan-Go et al, 1996). The concentration column shows treatment concentrations of the drugs.…”