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

The pharmacological response to vitamin K1 (Konakion) in anticoagulated (prothrombin complex activity less than 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 K1 (0.5 mg/kg) and declined at a rate indicating complete inhibition of clotting factor synthesis. A different response to vitamin K1 (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 K1(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 K1 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. less than 30%). In conclusion, we have found that brodifacoum and difenacoum are both more potent and persistent antagonists of vitamin K1 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.