Pharmacokinetics of the warfarin enantiomers in rats

Abstract

The pharmacokinetics of elimination and anticoagulant action of the R(+) and S(-) enantiomers of warfarin were determined in individual adult male Sprague- Dawley rats. A 12 mg/kg dose of one of the enantiomers and a tracer dose of racemic ¹⁴C -warfarin were injected intravenously, and the same doses of the other enantiomer and the tracer were administered 3 weeks later to the same animals. The apparent biological half- life of racemic warfarin ranged from about 6 to 18 hr and was very reproducible in individual animals. The ranges of the biological half-lives of R(+) and S(-)-warfarin were 4.9–9.6 hr and 7.7–21.6hr, respectively. There is a strong positive correlation between the half- life of each enantiomer in individual rats; the ratio of these half- lives, S(-):R(+), is 1.87 (sd 0.21, n=10). The apparent half- life of racemic warfarin in individual rats is in very good agreement with the half- life predicted from the sum of the plasma concentrations of R(+)-andS(−)-warfarin at various times after injection. There was no significant difference in the apparent volumes of distribution of R(+)-,S(-)-, and racemic warfarin. There was a pronounced intersubject variation in the relative potency of the two enantiomers; the ratio R(+):S(-) of the plasma concentrations required to decrease the synthesis rate of prothrombin complex activity by one-half ranged from 0.7 to 6.3, with a mean of 2.2.