EFFECT OF FUROSEMIDE ON PLASMA CLEARANCE, ANTICOAGU-LANT EFFECT AND PROTEIN BINDING OF WARFARIN IN RATS

Abstract

The effect of furosemide on the elimination, anticoagulant effect and the in vitro and in vivo protein bindings of warfarin was examined in rats. The pharmacokinetic parameters of warfarin and prothrombin complex activity (PCA) after a single i.v. coadministration with warfarin (1.2 mg/kg) and furosemide (1.67 mg/kg) were not significantly different as compared with those in the group injected warfarin alone; however when coadministered with 5 mg/kg of furosemide, the elimination rate constant was significantly increased and PCA was markedly enhanced beyond 60 h after administration. The concurrent treatment with warfarin and a higher dose (10 mg/kg) of furosemide caused an increase in the anticoagulant effect of warfarin even at earier periods after administration. Both the unbound warfarin concentration in serum at 30 min and the amount of warfarin extracted into liver at 2 h after a single i.v. dosing in the coadministered group were significantly increased as compared with those in the group received warfarin alone. Results from in vitro binding studies using bovine serum albumin and rat plasma showed a typical competitive nature of protein binding of warfarin and furosemide at the same binding sites. These results suggest that the interactions, such as the displacement of warfarin binding at albumin binding sites, between warfarin and furosemide are produced, when a high dose of furosemide was coadministered.