Paracetamol (acetaminophen) warfarin interaction: NAPQI, the toxic metabolite of paracetamol, is an inhibitor of enzymes in the vitamin K cycle
Henk H.Thijssen1, Berry A. Soute2, Lily M.Vervoort1, Jolanda G. Claessens3
Departments of 1Pharmacology and 2Biochemistry, University of Maastricht, Maastricht,The Netherlands 3Anticoagulation Center Maastricht, Maastricht,The Netherlands
Summary Paracetamol (acetaminophen) is generally considered to be theanalgesic of choice for patients undergoing oral anticoagulanttherapy.Occasionally, however, interactions have been reportedwith therapeutic doses of the analgesic, e.g. if the drug is takenfor a longer period of time.The mechanism of this interactionis not clearly understood.We investigated the effects of paracetamoland its toxic metabolite N-acetyl-para-benzoquinoneimine(NAPQI) on in vitro vitamin K-dependent γ-carboxylase(VKD-carb) and vitamin K epoxide reductase (VKOR) activities.Paracetamol had no effect in either enzymatic reactions.NAPQI, on the other hand, appeared to interfere with VKDBlood carb activity via two mechanisms; 1) oxidation of the cofactorvitamin K-hydroquinone, 2) inactivation of the enzyme. Theinactivation, in micromolar ranges, is not reversible and may bethe result of covalent binding of NAPQI with functional aminoacids. NAPQI also inhibited VKOR, but at higher concentrations.Unexpectedly, N-acetylcysteine was found to inhibitVKOR activity at concentrations that are obtained during rescuetherapy of paracetamol intoxication.We conclude that, thepotentiation of the oral anticoagulant effect by paracetamol islikely to result from NAPQI-induced inhibition of enzymes ofthe vitamin K cycle, particularly VKD-carb.