Clofibrate displaces warfarin from plasma proteins in man: an example of a pure displacement interaction

Clofibrate is known to potentiate the anticoagulant effect of warfarin during chronic administration. We examined the disposition of racemic warfarin in four healthy volunteers before and during clofibrate coadministration using an intravenous-continuous oral sequence of warfarin administration. An interaction between warfarin and clofibrate, evidenced by longer prothrombin and prothrombin-proconvertin times, was seen in all four subjects. Clofibrate caused a displacement of warfarin from plasma protein binding sites, with a 13% increase in the free drug fraction in plasma. As predicted from theoretical considerations, this displacement resulted in a small (18%) increase in the steady-state volume of distribution, and an increase in total plasma clearance, which, for warfarin, is independent on the free fraction of drug in plasma. The net effect of these changes is that the free concentration of warfarin was not changed during clofibrate coadministration, although total plasma concentrations were lower. This study documents the occurrence in man of a displacement pharmacokinetic interaction between clofibrate and warfarin. However, this pharmacokinetic interaction does not account for the clinical interaction between the two drugs, since free warfarin concentrations are unchanged.