Pharmacokinetics of warfarin enantiomers: A search for intrasubject correlations

Abstract

The total body clearance of single doses of R(+)‐, S(−)‐, and racemic warfarin and the plasma concentration‐anticoagulant effect curves for these drugs were determined in 10 healthy men, 21 to 51 yr old. This information was used to calculate the steady‐state dose required to decrease prothrombin complex activity to about 30% of normal. This dose (mean ± SD in mg/70 kg/day) is 17.8 ± 9.3 for R(+)‐warfarin, 6.63 ± 2.19 for S(−)‐warfarin, and 9.4 ± 1.7 for racemic warfarin. There is a correlation between the maintenance doses of racemic and S(−)‐warfarin (r = 0.89, p < 0.01) but not between those of racemic and R(+)‐warfarin (r = 0.30, NS). According to these calculations, the maintenance dose of racemic warfarin required by an individual patient may be a useful predictor of the maintenance dose of S(−)‐warfarin which will produce a comparable degree of anticoagulation. No such predictability is evident with respect to R(+)‐warfarin. The slopes of the log plasma concentration‐anticoagulant effect curves for R(+)‐and S(−)‐warfarin differ significantly. Therefore, the potency ratio of these enantiomers is dose‐and concentration‐dependent.