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  • Title: The relationship between the vitamin K cycle inhibition and the plasma anticoagulant response at steady-state S-warfarin conditions in the rat.
    Author: Mosterd JJ, Thijssen HH.
    Journal: J Pharmacol Exp Ther; 1992 Mar; 260(3):1081-5. PubMed ID: 1545379.
    Abstract:
    The relationship between the inhibition of the vitamin K cycle and the inhibition of the vitamin K-dependent clotting factor synthesis was studied in the rat under a controlled rate of S-warfarin administration. Steady state of drug disposition was achieved from beyond day 2 and stable anticoagulation was achieved from beyond days 3 to 4. Doses up to 0.5 micrograms/kg/h were without effect, whereas 3 micrograms/kg/h reduced prothrombin complex activity to about 10%. Factor II and factor VII activity were equally suppressed as prothrombin complex activity. The concentration-effect relationship for steady-state S-warfarin plasma concentration and the inhibition of clotting factor synthesis revealed a steep sigmoidal response relationship (IC50 = 0.21 +/- 0.01 micrograms/ml, Hill slope = 2.07 +/- 0.3). Contrary to this, the target enzyme vitamin K1 2,3-epoxide reductase showed a dose-dependent response for the entire dose range. The sigmoidal effect relationship for plasma S-warfarin and enzyme inhibition showed a slope of 0.81 +/- 0.07 with IC50 = 16 +/- 1 ng/ml. The results demonstrate a reserve capacity for the coumarin-sensitive reductase; at least 70% of the hepatic vitamin K1 2,3-epoxide reductase activity has to be eliminated before the vitamin K-dependent carboxylation of the clotting factors objectively becomes compromised. In the study, the microsomal warfarin binding sites were compared with the vitamin K1 2,3-epoxide reductase activity, and a strict 1 to 1 relationship was found supporting the relationship between both.(ABSTRACT TRUNCATED AT 250 WORDS)
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