Pharmacokinetics of the enantiomers of acenocoumarol in man.

Abstract

1 The pharmacokinetics of R(+)‐, S(‐)‐ and R,S(+/‐)‐acenocoumarol were studied in healthy volunteers after administration of single oral and intravenous doses. 2 After both oral and i.v. administration of either enantiomer in a dose of 0.25 mg/kg, the concentrations of R(+) found in the plasma were much higher than those of S(‐). This indicates that the observed differences are not related to stereoselective absorption. 3 After intravenous administration of 25 mg of each enantiomer and the racemate, the total plasma clearance of S(‐) was about 10 times that of R(+). The clearance of the racemate was between that of the enantiomers. 4 The apparent elimination half‐life of S(‐) was much shorter than those of R(+) and the racemate, which were similar. 5 The apparent volume of distribution VdSS of S(‐) acenocoumarol was 1.5 to 2 times that of R(+). 6 Measurements of the extent of binding to serum proteins, made in vitro at much higher concentrations than those observed in vivo, revealed no differences between the two enantiomers and the racemate. 7 The results indicate that the greater anticoagulant potency of R(+) compared with S(‐) acenocoumarol can be explained mainly by stereoselective differences in their metabolic clearance. 1981 The British Pharmacological Society