Stereoselective drug distribution and anticoagulant potency of the enantiomers of phenprocoumon in rats.
The elimination, distribution and anticoagulant activity of S(-)-, R(+)-, and R,S(+/-)- phenoprocoumon were determined in male Wistar-Lewis rats after intravenous injection of a single dose of 0.6 mg kg-1. From the plasma concentrations which elicited the same anticoagulant effect, S(-)-phenprocoumon was 4 to 5 times more potent than R(+)-phenprocouman. The potency of the racemate was between those of the enantiomers. The mean biologic half-life of the S(-)-enantiomer was shorter (12-5 h) than that of R(+)-phenprocoumon (17-8 h). No differences were observed in the apparent volume of distribution. However, the mean liver:plasma concentration ratio was higher for the S(-)-(6-9) than for the R(+)-enantiomer (5-2). At a total concentration of 16-8 microgram ml-1 the percentage of unbound drug in rat serum was significantly higher for the S(-)- (1-13%) than that for the R(+)-enantiomer (0.76%). Values obtained for the racemate were always between those of the enantiomers. It is concluded that stereoselective differences in the distribution between plasma and liver, and consequently in the rate of elimination are most likely due to stereoselective differences in serum protein binding. The greater anticoagulant potency of the S(-)- over the R(+)-enantiomer, cannot be explained primarily by the observed pharmacokinetic differences.
Stereoselective drug distribution and anticoagulant potency of the enantiomers of phenprocoumon in rats. The elimination, distribution and anticoagulant activity of S(-)-, R(+)-, and R,S(+/-)- phenoprocoumon were determined in male Wistar-Lewis rats after intravenous injection of a single dose of 0.6 mg kg-1. From the plasma concentrations which elicited the same anticoagulant effect, S(-)-phenprocoumon was 4 to 5 times more potent than R(+)-phenprocouman. The potency of the racemate was between those of the enantiomers. The mean biologic half-life of the S(-)-enantiomer was shorter (12-5 h) than that of R(+)-phenprocoumon (17-8 h). No differences were observed in the apparent volume of distribution. However, the mean liver:plasma concentration ratio was higher for the S(-)-(6-9) than for the R(+)-enantiomer (5-2). At a total concentration of 16-8 microgram ml-1 the percentage of unbound drug in rat serum was significantly higher for the S(-)- (1-13%) than that for the R(+)-enantiomer (0.76%). Values obtained for the racemate were always between those of the enantiomers. It is concluded that stereoselective differences in the distribution between plasma and liver, and consequently in the rate of elimination are most likely due to stereoselective differences in serum protein binding. The greater anticoagulant potency of the S(-)- over the R(+)-enantiomer, cannot be explained primarily by the observed pharmacokinetic differences.