title: The relationship between the vitamin K cycle inhibition and the plasma anticoagulant response at steady-state S-warfarin conditions in the rat.
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)
authors.affiliation: Department of Pharmacology, University of Limburg, Maastricht, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Mosterd
authors.forename: H H
authors.initials: HH
authors.lastname: Thijssen
mesh_terms: D000818:Animals; D001665:Binding Sites; D001777:Blood Coagulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D006899:Mixed Function Oxygenases / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D014812:Vitamin K / Q000037:antagonists & inhibitors*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D014812:Vitamin K; D014859:Warfarin; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases