A comparison of vitamin K antagonism by warfarin, difenacoum and brodifacoum in the rabbit

Abstract

The pharmacological response to vitamin K 1 (Konakion ’) in anticoagulated (prothrombin complex activity <30%) New Zealand white rabbits was determined by measuring prothrombin complex activity (P.C.A.) in peripheral plasma. In animals pretreated with either brodifacoum (1 mg/kg or 10 mg/kg) or difenacoum (0.85 mg/kg or 8.5 mg/kg) P.C.A. reached a maximum 4 hr after administration of vitamin K 1 (0.5 mg/kg) and declined at a rate indicating complete inhibition of clotting factor synthesis. A different response to vitamin K 1 (0.5 mg/kg) was observed in rabbits pretreated with warfarin (63 mg/kg); after an initial rise P.C.A. appeared to plateau for 11 hr and then fall at a rate which indicated incomplete inhibition of clotting factor synthesis. The response to several doses of vitamin K 1 (0.5, 1, 2.5 and 5.0 mg/kg) was investigated in the same group of brodifacoum (1 mg/kg) anticoagulated animals. There was a linear relationship between the duration of clotting factor synthesis and the logarithm of the dose of the vitamin K; the pharmacological half-life of vitamin K 1 was only 1.7 ± 0.1 hr. The duration of action of brodifacoum and difenacoum was much longer than that of warfarin. Six weeks after administration of brodifacoum (1 mg/kg) animals were still anticoagulated (P.C.A. < 30%). In conclusion, we have found that brodifacoum and difenacoum are both more potent and persistent antagonists of vitamin K 1 than warfarin in vivo. In cases of poisoning with these compounds it will be necessary to give repeated and frequent doses of vitamin K to maintain clotting factor synthesis.