Target-based warfarin pharmacokinetics in the rat: the link with the anticoagulant effect.

Warfarin and congeners bind tightly to the target enzyme vitamin K epoxide reductase. In this study the impact of the target binding on the warfarin pharmacokinetics in plasma and liver of the rat was estimated. Furthermore, the effect of warfarin pharmacokinetics on the time course of inhibition of vitamin K epoxide reductase was followed to find a link with the effect in time on the vitamin K-dependent clotting factor synthesis. Biochemical parameters, drug tissue levels and plasma coagulation activity prothrombin time were followed in normal and phenobarbitone (PB)-treated rats for 12 days after a single dose of S-warfarin (0.5 mg/kg). Warfarin accumulated to saturation (40-50 pmol/mg of protein) in liver microsomes to remain prolongedly bound and the half-life of elimination exceeded 7 days. PB-treated rats were not found to differ in this respect. In parallel with the steady increase of microsomal-free warfarin binding sites the ex vivo vitamin K epoxide reductase activity recovered, from 10% control activity at t = 3 hr to 70% at t = 12 days. PB-treated rats showed a 1.8-fold higher recovery rate in free enzyme. Blood coagulation was affected during the time in which the ex vivo vitamin K epoxide reductase activity was less than 20% of normal activity. The ex vivo reductase inhibition showed a sigmoidal effect relationship for plasma S-warfarin. Emax appeared to be significantly less than 100% (95% confidence intervals; 83-91%).(ABSTRACT TRUNCATED AT 250 WORDS)