Enantioselective Structure-pharmacokinetic Relationships of Ring Substituted Warfarin Analogues in the Rat

Abstract

Abstract The enantiomer specific pharmacokinetics of ring substituted warfarin analogues have been studied in the rat after the administration of 2 mg kg−1 of the racemates. The stereoselective differences observed were due to stereoselective plasma protein binding and stereoselective intrinsic hepatic clearance. Greater binding was observed for the S-enantiomers except for 2′-substituted analogues where the R-enantiomers were more tightly bound. The stereoselectivity in the binding ranged up to a factor of about 4. All substituted warfarins showed a higher intrinsic clearance than warfarin. Enantiomer selectivity depended on the position of the substituent; warfarin and 3′-substituted analogues showed R > S; 4′-and 2′ substituted warfarins showed S > R stereoselectivity. Exceptions to this generality were seen for 4′-methoxy-and 4′-methylwarfarin which did not show stereoselective hepatic clearance.