The elimination, distribution and anticoagulant activity of S( -)-, R( +)-, and R,S( i)-phenprocoumon were determined in male Wistar-Lewis rats after intravenous injection of a single dose of 0.6mg kg-l. From the plasma concentrations which elicited the same anticoagulant effect, S( -)-phenprocoumon was 4 to 5 times more potent than R( +)-phenprocoumon. 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 16.8pg ml-l 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 Dotencv of the S(-)-over the R(+)-enantfomer, cannot be explained primarily by the observed pharmacokinetic differences.

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The interaction of phenylbutazone with the enantiomers and racemic [3H]phenprocoumon was studied in male inbred Wistar-Lewis rats following a single i.v. dose of the three forms of phenprocoumon and chronic oral treatment with phenylbutazone (average plasma concentration of about 60 microgram/ml). Phenylbutazone augmented the anticoagulant effect of R(+), S(-), and R, S(+/-) phenprocoumon to a similar extent. The free fraction of drug in the plasma of the enantiomers and racemic phenprocoumon increased in the presence of phenylbutazone. However, the rate of elimination of total drug from plasma and liver and the distribution between liver and plasma of all three forms of phenprocoumon remained nearly unaffected by phenylbutazone. Thus there is no evidence for a stereoselective drug interaction between phenprocoumon and phenylbutazone. For racemic [oH]phenprocoumon it was possible to follow the kinetics of free drug in plasma and liver along with the time course of anticoagulant activity. In these studies, free drug concentrations in plasma and liver increased during treatment with phenylbutazone, but the elimination rate constant of free racemic phenprocoumon in plasma and liver remained essentially unchanged. Phenylbutazone markedly decreased the volume of distribution referenced to free drug and the clearance of free phenprocoumon (i.e., intrinsic metabolic clearance). Whereas the total (bound and unbound) drug concentration--effect relationship in plasma and liver was shifted to the left in rats treated with phenylbutazone, such shift was not seen in the free drug concentration--response relationship. In conclusion, the increase in the free concentration of phenprocoumon in plasma and liver and the concomitant decrease in the clearance of free drug are the mechanisms responsible for the marked and sustained enhancement of the anticoagulant effect which follows treatment with phenbutazone.

The elimination, distribution and anticoagulant activities of the enantiomers of phenprocoumon were studied in rats following enzyme induction by phenobarbital (pretreatment with 75 mg·kg^–1 for 4 days) and enzyme inhibition by chloramphenicol (100 mg·kg^–1 1 h prior to the injection of phenprocoumon and then 50 mg·kg^–1 every 12 h). Pretreatment with phenobarbital increased the rate of elimination and decreased the total anticoagulant effect per dose of both enantiomers. It also caused a slight reduction of the liver/plasma concentration ratio of the enantiomers due to the increase of the liver weight and a significant enhancement of the synthesis rate of prothrombin complex activity in non-anticoagulated rats. Chloramphenicol decreased the rate of elimination and enhanced the total anticoagulant effect per dose of both enantiomers. The distribution between plasma and liver remained unaffected. Thus, in rats neither the induction of the phenprocoumon metabolism by phenobarbital nor its inhibition by chloramphenicol appears to be stereoselective.