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DRUG INFORMATION ROUNDS

Does Metronidazole Interact with CYP3A Substrates by Inhibiting Their Metabolism Through This Metabolic Pathway? Or Should Other Mechanisms Be Considered?

Cardiology/Critical Care Pharmacist, Peter Lougheed Centre, Calgary, Alberta, Canada

Melinda M Neuhauser, PharmD

Clinical Pharmacy Specialist, National Institute of Allergy and Infectious Diseases, Clinical Center Pharmacy Department, National Institutes of Health, Bethesda, MD

Scott R Penzak, PharmD

Director, Clinical Pharmacokinetics Research Laboratory, Clinical Center Pharmacy Department, National Institutes of Health

Reprints: Dr. Penzak, Clinical Pharmacokinetics Research Laboratory, Clinical Center Pharmacy Department, National Institutes of Health, Building 10 1N 257, Bethesda, MD 20892, fax 301/496-0210, spenzak{at}mail.cc.nih.gov

OBJECTIVE: To explore whether CYP3A inhibition by metronidazole is the primary mechanism by which metronidazole interacts with coadministered CYP3A substrates.

DATA SOURCES: Literature was accessed using the MEDLINE database (1966–February 2007). Search terms included metronidazole, cytochrome P450, CYP3A4, CYP3A5, drug interactions, and P-glycoprotein. References from pertinent articles, as well as from tertiary sources, were also considered.

STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources that were published in English were evaluated. Case reports and pharmacokinetic evaluations were included.

DATA SYNTHESIS: Elevated plasma concentrations and toxicities have been reported for a number of CYP3A substrates including amiodarone, carbamazepine, quinidine, tacrolimus, and cyclosporine when administered with metronidazole. This has led to the widespread belief that metronidazole is a significant inhibitor of CYP3A4. However, 4 pharmacokinetic studies conducted in humans showed that metronidazole did not increase plasma concentrations of the CYP3A substrates midazolam, erythromycin, cyclosporine, and alprazolam, thereby refuting the suggestion that metronidazole is a CYP3A4/5 inhibitor.

CONCLUSIONS: Drug interactions between metronidazole and certain CYP3A substrates do not appear to result from CYP3A4/5 inhibition by metronidazole. Until any mechanism is identified by which metronidazole alters the disposition of certain CYP3A substrates, drug interactions with this agent should be assessed on a case-by-case basis, taking into account the safety index of the coadministered drug and the availability of equally effective substitutes for either metronidazole or the drug with which it putatively interacts.

Key Words: cytochrome P450, drug interactions, metronidazole

Published Online, March 20, 2007. www.theannals.com, DOI 10.1345/aph.1H401