TARGET-BASED WARFARIN PHARMACOKINETICS IN THE RAT - THE LINK WITH THEANTICOAGULANT EFFECT

Warfarin and congeners bind tightly to the target enzyme vitamin K epo xide 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 cou rse of inhibition of vitamin K epoxide reductase was followed to find a link with the effect in time on the vitamin K-dependent clotting fac tor synthesis. Biochemical parameters, drug tissue levels and plasma c oagulation activity prothrombin time were followed in normal and pheno barbitone (PB)-treated rats for 12 days after a single dose of S-warfa rin (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 micro somal-free warfarin binding sites the ex vivo vitamin K epoxide reduct ase activity recovered, from 10% control activity at t = 3 hr to 70% a t 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 whic h the ex vivo vitamin K epoxide reductase activity was less than 20% o f normal activity. The ex vivo reductase inhibition showed a sigmoidal effect relationship for plasma S-warfarin. E(max) appeared to be sign ificantly less than 100%(95% confidence intervals; 33-91%). To conclud e, the study disclosed I)warfarin binding to microsomal vitamin K epox ide reductase to retard strongly its elimination from liver tissue and 2) there to be a small fraction, about 10%, of the vitamin K epoxide reductase which is not irreversibly inhibited. Whether it is this frac tion which is linked to the vitamin K-dependent clotting factor synthe sis remains to be answered.