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The Mechanism and Drug Interaction - Metronidazole (Flagyl) and Warfarin (Coumadin, Jantoven)


  • The metabolism of metronidazole is largely undetermined.
  • The available evidence suggests metronidazole inhibits CYP2C9, the enzyme responsible for S-warfarin metabolism.
  • Delayed metabolism of warfarin enhances the anticoagulant effect and increases the likelihood of bleeding complications.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed: August 2015


  • Warfarin (Coumadin; Jantoven) is an oral anticoagulant most commonly used for the prevention and treatment of thromboembolic events (blood clots) in patients with atrial fibrillation, prosthetic heart valves, venous thrombosis and/or pulmonary embolism.1  Metronidazole (Flagyl) is an oral antibiotic most commonly used to treat a number of gastrointestinal and genitourinary infections.2-4

    The concern with concurrent therapy is the reporting of clinically significant increases in INR when patients taking warfarin are prescribed metronidazole.5,6  Warfarin is a racemic (equal) mixture of two enantiomers, S-warfarin and R-warfarin.  While both enantiomers are pharmacologically active, S-warfarin is known to be responsible for the majority of the clinical effect and toxicity of warfarin, as it is five times more potent than R-warfarin.  Both S-warfarin and R-warfarin are metabolized by cytochrome P450 (CYP) enzymes (a group of intestinal and liver enzymes responsible for drug metabolism).  Metronidazole's metabolism and its specific effect on warfarin are not as clearly defined.  Metronidazole has been reported to have a stereoselective inhibition of S-warfarin metabolism which suggests possible inhibition of CYP2C9, the enzyme responsible for S-warfarin metabolism.7,8  Inhibition of CYP2C9 by metronidazole would delay metabolism of S-warfarin; this would lead to an enhanced anticoagulant effect and increase the potential for bleeding complications.  Similarly, metronidazole has been reported to impair the clearance of phenytoin, another CYP2C9 substrate.9 These data were reported prior to widespread knowledge of CYP isoforms. 

    Unfortunately, none of the available studies have determined the effects of metronidazole on CYP2C9 specifically and they did not implicate CYP2C9 by name.  However, this remains the most prominent hypothesis for the mechanism of the interaction between metronidazole and warfarin.  Other hypotheses that have been suggested include displacement of protein-bound S-warfarin by metronidazole and modulation of drug transporters by metronidazole.8,10,11  The evidence for these last two hypotheses is meager, at best.


    1. Ageno W et. al.  Oral Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis 9th ed:  American College of Chest Physicians evidence-based clinical practice guidelines.  Chest   2012;141(2)(Suppl):e44S-e88S.
    2. Gerding DN, Muto CA, Owens RC Jr.  Treatment of clostridium difficile infection.  Clin Infect Dis  2008;46(Suppl 1):S32-S42.
    3. Solomkin JS, Mazuski JE, Baron EJ, et. al.  Guidelines for the selection of anti-infective agents for complicated intra-abdominal infections.  Clin Infect Dis  2003;37(8):997-1005.
    4. Centers for Disease Control and Prevention, Workowski KA, Berman SA.  Sexually transmitted diseases treatment guidelines, 2006.  MMWR Recomm Rep  2006;55(RR-11):1-94.
    5. Dean RP, Talbert RL.  Bleeding associated with concurrent warfarin and metronidazole therapy.  Drug Intell Clin Pharm  1980;14864-866.
    6. Kazmier FJ.  A significant interaction between metronidazole and warfarin.  May Clin Proc.  1976;51:782-784.
    7. O'Reilly RA.  The stereoselective interaction of warfarin and metronidazole in man.  N Engl J Med.  1976;295(7):354-357.
    8. Yacobi A, Lai CM, Levy G.  Pharmacokinetic and pharmacodynamic studies of acute interaction between warfarin enantiomers and metronidazole in rats.  J Pharmacol Exp Ther  1984;231:72-9.
    9. Blyden GT, Scavone JM, Greenblatt DJ.  Metronidazole impairs the clearance of phenytoin but not of alprazolam or lorazepam.  J Clin Pharmacol  1988;28:240-245.
    10. Page RL 2nd, Klem PM, Rogers C.  Potential elevation of tacrolimus trough concentrations with concomitant metronidazole therapy.  Ann Pharmacother  2005;39:1109-1113.
    11. Roedler R, Neuhauser MM, Penzak SR.  Does metronidazole interact with CYP3A substrates by inhibiting their metabolism through this metabolic pathway?  Or should other mechanisms be considered?.  Ann Pharmacother 2007;41:653-658.1

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