ENANTIOSELECTIVE STRUCTURE-PHARMACOKINETIC RELATIONSHIPS OF RING SUBSTITUTED WARFARIN ANALOGS IN THE RAT

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.