Interaction of clofibrate with warfarin. I. Effect of clofibrate on the disposition of the optical enantiomorphs of warfarin

Four volunteers each received single oral doses of the R and S enantiomorphs of warfarin on separate occasions, both before and during clofibrate coadministration. Three of the subjects showed evidence for a drug interaction as manifested by an increase in the hypoprothrombinemic response to the S enantiomorph during clofibrate coadministration (0.10>p>0.05). No changes were observed in the response to the R enantiomorph. The volume of distribution of the R enantiomorph was increased (0.01>p> 0.005), as was the plasma clearance (0.10>p> 0.05), in all four subjects during clofibrate coadministration. No significant changes were found in the volume of distribution or clearance of the S enantiomorph. This study indicates that differential changes in the clearance of the enantiomorphs of warfarin are not the mechanism responsible for the interaction of clofibrate with warfarin. Although the results indicate that plasma protein displacement of warfarin occurs in vivo,it can be concluded that the mechanism underlying the long-term enhanced hypoprothrombinemic effect of warfarin in the presence of clofibrate is of a pharmacodynamic nature.This investigation was supported in part by NIH Grants GM22209 and 1-PO1-HL-15833. T. D. B. is a recipient of a Merck, Sharp & Dohme International Fellowship in Clinical Pharmacology. T. F. B. is a recipient of a Pharmaceutical Manufacturers Association Foundation Faculty Development Award.