Does metronidazole interact with CYP3A substrates by inhibiting their metabolism through this metabolic pathway? Or should other mechanisms be considered?

Rhonda Roedler, Melinda M. Neuhauser, Scott Robert Penzak

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)653-658
Number of pages6
JournalAnnals of Pharmacotherapy
Volume41
Issue number4
DOIs
StatePublished - 1 Apr 2007

Fingerprint

Cytochrome P-450 CYP3A
Metronidazole
Metabolic Networks and Pathways
Drug Interactions
Cyclosporine
Pharmacokinetics
Alprazolam
Quinidine
Amiodarone
Information Storage and Retrieval
Midazolam
Carbamazepine
P-Glycoprotein
Tacrolimus
Erythromycin
MEDLINE
Pharmaceutical Preparations
Cytochrome P-450 Enzyme System
Databases

Keywords

  • Cytochrome P450
  • Drug interactions
  • Metronidazole

Cite this

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title = "Does metronidazole interact with CYP3A substrates by inhibiting their metabolism through this metabolic pathway? Or should other mechanisms be considered?",
abstract = "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.",
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Does metronidazole interact with CYP3A substrates by inhibiting their metabolism through this metabolic pathway? Or should other mechanisms be considered? / Roedler, Rhonda; Neuhauser, Melinda M.; Penzak, Scott Robert.

In: Annals of Pharmacotherapy, Vol. 41, No. 4, 01.04.2007, p. 653-658.

Research output: Contribution to journalArticle

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T1 - Does metronidazole interact with CYP3A substrates by inhibiting their metabolism through this metabolic pathway? Or should other mechanisms be considered?

AU - Roedler, Rhonda

AU - Neuhauser, Melinda M.

AU - Penzak, Scott Robert

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N2 - 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.

AB - 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.

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