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

Abstract

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 gamma-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.

Comparison of warfarin sensitivity between rat and bird species

“…The pharmacological target of these rodenticides is vitamin K 2,3-epoxide reductase (VKOR), which catalyzes the reduction of vitamin K 2,3-epoxide (VKO) and vitamin K (Figure 1). Because reduced vitamin K is required for the post-translational formation of γ-carboxyglutamyl residues from Glu residues in clotting factors II, VII, IX, and X (Suttie and Nelsestuen , 1980), the inhibition of VKOR by coumarin derivatives causes lethal hemorrhages in rodents (Thijssen et al, 2004;Cain et al, 1998). Meanwhile, coumarin derivative anticoagulants are metabolized by cytochrome P450 (CYP), which consists of a large number of isoforms.…”

Elevated Warfarin Metabolism in Warfarin-Resistant Roof Rats (Rattus rattus) in Tokyo

“…It inhibits coagulation of blood by inhibiting vitamin K epoxide reductase (VKOR) activity (Thijssen et al, 2004). An inadequate supply of vitamin K blocks the production of prothrombin and causes hemorrhaging.…”

Protein binding interaction of warfarin and acetaminophen in presence of arsenic and of the biological system

“…However, it is important to note that the clinical significance of the acetaminophen-warfarin interaction is not without controversy. The mechanism of this interaction has only recently been elucidated (Thijssen et al, 2004) and likely results from the independent inhibitory effect of an acetaminophen metabolite on enzymes of the vitamin K cycle. Although several case reports and controlled studies have reported that acetaminophen potentiates the anticoagulant effect of warfarin (Hylek et al, 1998), others have not found a clinically relevant interaction (Fattinger et al, 2002).…”