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

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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.