Enzymatic shunting: resolving the acetaminophen-warfarin controversy

Observational studies in patients have shown a dose-dependent enhancement of the anticoagulant effect of warfarin by acetaminophen whereas pharmacodynamic studies in healthy human volunteers have shown no such effect. This controversy is further intensified because any interaction between acetaminophen and racemic warfarin can involve only the weaker R-warfarin enantiomer. Certain drugs exclusively competing for the metabolism of R-warfarin enhance the anticoagulant effect of racemic warfarin and others do not. Because R-warfarin is a weak inhibitor of vitamin K epoxide reductase and is metabolized by cytochrome P450 (CYP) 1A2 and 3A4, it is hypothesized that simultaneous competition with R-warfarin for CYP1A2 and 3A4 is required for drug interactions to be clinically significant with compounds exclusively affecting the R enantiomer, such as acetaminophen. The discrepant observations in the literature regarding the clinical significance of the acetaminophen-warfarin interaction may be resolved if the hepatic enzyme activity of CYP1A2 and 3A4 is enhanced relative to CYP2E1 and the nonoxidative pathways of glucuronidation and sulfation responsible for acetaminophen metabolism. Conditions such as aging and tissue hypoxia alter the relative activity of these enzymatic pathways in vitro and in small human studies. These phenomena may be manifested clinically when acetaminophen is administered to older anticoagulated patients and those with conditions that affect cardiac output such as atrial fibrillation and congestive heart failure. Verifying this hypothesis may provide insight into the clinically relevant interplay between common conditions as they affect oxidative and nonoxidative pathways of drug metabolism.