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Comparative pharmacokinetics of coumarin anticoagulants XLV: Pharmacokinetic and pharmacodynamic studies of acute interaction between warfarin and phenylbutazone in rats.

A comprehensive investigation of the effect of phenylbutazone on warfarin pharmacokinetics and anticoagulant activity was carried out in rats to identify and quantify various aspects of the interaction between these drugs. Adult male rats received intravenous racemic warfarin alone and together with phenylbutazone in a crossover experiment. Prothrombin complex activity and the plasma concentrations of phenylbutazone and of free and total (free plus protein-bound) warfarin were determined repeatedly for up to 60 hr. The total plasma clearance, the apparent volume of distribution, and the disposition rate constant (β) of warfarin were significantly increased and the intrinsic plasma warfarin clearance was significantly decreased during phenylbutazone administration. Phenylbutazone decreased the serum protein binding of warfarin both in vitro and in vivo, but the in vivo effect was much more pronounced, apparently due to the displacing effect of phenylbutazone metabolite(s). Phenylbutazone alone had no apparent effect on prothrombin complex activity in vitro but caused a modest, yet statistically significant, anticoagulant effect in vivo. The anticoagulant effect-plasma warfarin concentration curves for total and free warfarin were shifted to a considerably lower concentration range during phenylbutazone treatment. Thus, the interaction between phenylbutazone and warfarin involves at least three processes: an inhibition of warfarin biotransformation (decreased intrinsic clearance); displacement of warfarin from plasma protein binding sites (increased free fraction); and apparent potentiation of the anticoagulant action produced by a given plasma warfarin concentration. The latter may have been caused, at least in part, by a direct anticoagulant effect of phenylbutazone and/or its metabolite(s). The net effect of decreased protein binding and decreased intrinsic clearance was an increase in the total plasma warfarin clearance. The results of this investigation demonstrate that drug interactions can be complex and multifactorial.