Effect of Mibefradil on CYP3A4 In Vivo

• Published in: Journal of clinical pharmacology Vol. 43; no. 10; pp. 1091 - 1100
• Main Authors: Veronese, Maria L., Gillen, Lisa P., Dorval, Ellen P., Hauck, Walter W., Waldman, Scott A., Greenberg, Howard E.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-10-2003; SAGE Publications; Sage Science; Wiley Subscription Services, Inc
• Subjects: Adult; Antihypertensive agents; Biological and medical sciences; Breath Tests - methods; Carbon Radioisotopes; Cardiovascular system; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - drug effects; Cytochrome P-450 Enzyme System - metabolism; Drug Combinations; Drug Interactions; Erythromycin - administration & dosage; Erythromycin - analogs & derivatives; Erythromycin - metabolism; Erythromycin - pharmacokinetics; Erythromycin - urine; erythromycin breath test; General pharmacology; Humans; Intestines - enzymology; Liver - enzymology; Male; Medical sciences; Metabolic Clearance Rate - drug effects; Mibefradil; Mibefradil - administration & dosage; Mibefradil - blood; Mibefradil - pharmacokinetics; Midazolam - blood; Midazolam - pharmacokinetics; Molecular Probes; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Single-Blind Method; Human; Mibefradil; Healthy subject; Digestive system; Isozyme; Cytochrome P450; Liver; Calcium antagonist; Gut; Oral administration; Enzyme inhibitor; Metabolism; Enzymatic activity; Benzimidazole derivatives; Antihypertensive agent; Benzodiazepine derivatives; Drug interaction; Midazolam; Pharmacokinetics
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1177/0091270003256687

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 Cmax of midazolam 3‐fold, the AUC 8‐ to 9‐fold, and the t1/2 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.