THE LONG-TERM EFFECTS OF THE RODENTICIDE, BRODIFACOUM, ON BLOOD-COAGULATION AND VITAMIN-K METABOLISM IN RATS

1 The long-term (30 days) effects of a single dose of brodifacoum (0.2 mg kg-1, orally) on blood clotting activity and on liver parameters of the vitamin K cycle were investigated in rats. Maximal effect on blood clotting activity was seen on day one. On day seven blood clotting activity had returned to normal. 2 Liver microsomal vitamin KO reductase activity was maximally suppressed (10% of control activity) on day one, steadily recovered to about 40% on day 15 to remain at that level. The same time course was seen for the number of microsomal warfarin binding sites. 3 The persistent inhibition of the vitamin K cycle was also verified in vivo; following vitamin K administration (10 mg kg-1, i.v.) on day 30, the brodifacoum-treated rats accumulated vitamin KO in the liver. 4 Although clotting factor synthesis was normal, brodifacoum-treated rats were highly sensitive to warfarin. 5 Brodifacoum rapidly accumulated in the liver until the saturation of the microsomal binding site. Brodifacoum binding to the target prevented its elimination from the liver; liver content on day 30 was not different from day 7. 6 The results show (1) an over capacity for the hepatocellular vitamin K cycle, (2) a dissociation of the vitamin K epoxidation and the vitamin K-dependent carboxylation, (3) the 'superwarfarin' rodenticides to be extremely persistent due to their binding to the target.