Effect of mibefradil on CYP3A4 in vivo

Mibefradil, a calcium channel blocker, was removed from the market because of adverse drug interactions with coadministered CYP3A4 Substrates. This study examined the. effect of mibefradil on the activity of hepatic and intestinal CYP3A4 in vivo. employing the erythroinycin breath test (EBT) and oral midazolam pharmacokinetics. This was a two-period, single-blind, placebo-controlled crossover study in which 8 male volunteer were randomized to the order of receiving placebo and a single 100-mg oral dose of mibefradil. Oral midozolam was coodininistered with intravenous [C-14 N-methyl] erythromycin 1 hour after mibefradil/placebo administration. The EBT was performed 20 Minutes following erythrornycin administration. Blood and urine were collected during the 36 hours following probe drug administration for analysis of midozolam pharmacokinetics. Coadministration of mibefradil increased the C-max of midazolam 3-fold, the AUC 8- to 9-fold, and the t(1/2) 4-fold. Mibefradil coadministration decreased the amount Of exhaled (CO2)-C-14 in 6 of 8 Subjects, with a mean decrease of 25%. It was Concluded that a single oral dose of mibefradil significontly inhibits CYP3A4 in intestine and liver. These data support that adverse drug interactions involving mibefradil reflect inhibition of CYP3A4 in intestine and liver. Also, they suggest that the EBT while a valid probe of in vivo hepatic CYP3A4 activity, is a single time point measurement and maybe less sensitive than oral midazolom pharmocokinetics in detecting, CYP3A4 inhibition.