Paracetamol (acetaminophen) warfarin interaction: NAPQI, the toxic metabolite of paracetamol, is an inhibitor of enzymes in the vitamin K cycle

Henk H. Thijssen; Berry A. Soute; Lily M. Vervoort; Jolanda G. Claessens

doi:10.1160/TH04-02-0109

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 92(04): 797-802
DOI: 10.1160/TH04-02-0109

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Paracetamol (acetaminophen) warfarin interaction: NAPQI, the toxic metabolite of paracetamol, is an inhibitor of enzymes in the vitamin K cycle

Henk H. Thijssen

¹Department of Pharmacology

,

Berry A. Soute

²Department of Biochemistry, University of Maastricht, Maastricht, The Netherlands

,

Lily M. Vervoort

¹Department of Pharmacology

,

Jolanda G. Claessens

³Department of Anticoagulation Center Maastricht, Maastricht, The Netherlands

› Author Affiliations

Abstract

Summary

Paracetamol (acetaminophen) is generally considered to be the analgesic of choice for patients undergoing oral anticoagulant therapy. Occasionally, however, interactions have been reported with therapeutic doses of the analgesic, e.g. if the drug is taken for a longer period of time. The mechanism of this interaction is not clearly understood. We investigated the effects of paracetamol and 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 VKD-carb activity via two mechanisms; 1) oxidation of the cofactor vitamin K-hydroquinone, 2) inactivation of the enzyme. The inactivation, in micromolar ranges, is not reversible and may be the result of covalent binding of NAPQI with functional amino acids. NAPQI also inhibited VKOR, but at higher concentrations. Unexpectedly, N-acetylcysteine was found to inhibit VKOR activity at concentrations that are obtained during rescue therapy of paracetamol intoxication. We conclude that, the potentiation of the oral anticoagulant effect by paracetamol is likely to result from NAPQI-induced inhibition of enzymes of the vitamin K cycle, particularly VKD-carb.

Keywords

Oral anticoagulation - paracetamol - drug interaction - vitamin K-dependent factors

Full Text

References

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