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Effect of Mibefradil on CYP3A4 In Vivo

From the Division of Clinical Pharmacology, Departments of Medicine (Ms. Gillen, Ms. Dorval, Dr. Hauck, Dr. Greenberg) and Biochemistry and Molecular Pharmacology (Dr. Waldman) and the Kimmel Cancer Center (Dr. Veronese), Thomas Jefferson University, Philadelphia, Pennsylvania.

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 erythromycin breath test (EBT) and oral midazolam pharmacokinetics. This was a two-period, single-blind, placebo-controlled crossover study in which 8 male volunteers were randomized to the order of receiving placebo and a single 100-mg oral dose of mibefradil. Oral midazolam was coadministered with intravenous [¹⁴C N-methyl] erythromycin 1 hour after mibefradil/placebo administration. The EBT was performed 20 minutes following erythromycin administration. Blood and urine were collected during the 36 hours following probe drug administration for analysis of midazolam 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 ¹⁴CO₂ in 6 of 8 subjects, with a mean decrease of 25%. It was concluded that a single oral dose of mibefradil significantly 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 may be less sensitive than oral midazolam pharmacokinetics in detecting CYP3A4 inhibition.

Key Words: Mibefradil • drug interactions • midazolam pharmacokinetics • erythromycin breath test

Address for reprints: Howard E. Greenberg, MD, MS, FCP, Division of Clinical Pharmacology, Department of Medicine, Jefferson Medical College, 132 South 10th Street, 1170 Main, Philadelphia, PA 19107.

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