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.
  
  
  METHODS
  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.
  
  
  METHODS
  All articles identified from the data sources that were published in English were evaluated. Case reports and pharmacokinetic evaluations were included.
  
  
  RESULTS
  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.
authors: Peter Lougheed Centre, Calgary, Alberta, Canada.
authors: Rhonda
authors: R
authors: Roedler
authors: Melinda M
authors: MM
authors: Neuhauser
authors: Scott R
authors: SR
authors: Penzak
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D000525:Alprazolam / Q000378:metabolism / Q000493:pharmacokinetics; D000890:Anti-Infective Agents / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D006801:Humans; D008657:Metabolic Clearance Rate; D008795:Metronidazole / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000890:Anti-Infective Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D008795:Metronidazole; D051544:Cytochrome P-450 CYP3A; D000525:Alprazolam