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.
References:
- 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.
- Gerding DN, Muto CA, Owens RC Jr. Treatment of clostridium difficile infection. Clin Infect Dis 2008;46(Suppl 1):S32-S42.
- 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.
- 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.
- Dean
RP, Talbert RL. Bleeding associated with concurrent warfarin and
metronidazole therapy. Drug Intell Clin Pharm 1980;14864-866.
- Kazmier FJ. A significant interaction between metronidazole and warfarin. May Clin Proc. 1976;51:782-784.
- O'Reilly RA. The stereoselective interaction of warfarin and metronidazole in man. N Engl J Med. 1976;295(7):354-357.
- 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.
- 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.
- Page RL 2nd,
Klem PM, Rogers C. Potential elevation of tacrolimus trough
concentrations with concomitant metronidazole therapy. Ann
Pharmacother 2005;39:1109-1113.
- 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
