title: Enantioselective structure-pharmacokinetic relationships of ring substituted warfarin analogues in the rat.
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 greater than S; 4'- and 2' substituted warfarins showed S greater than R stereoselectivity. Exceptions to this generality were seen for 4'- methoxy- and 4'-methylwarfarin which did not show stereoselective hepatic clearance.
authors.affiliation: Dept of Pharmacology, University of Limburg, Maastricht, The Netherlands.
authors.forename: L G
authors.initials: LG
authors.lastname: Baars
authors.forename: M T
authors.initials: MT
authors.lastname: Schepers
authors.forename: J J
authors.initials: JJ
authors.lastname: Hermans
authors.forename: H J
authors.initials: HJ
authors.lastname: Dahlmans
authors.forename: H H
authors.initials: HH
authors.lastname: Thijssen
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D008297:Male; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014859:Warfarin / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D001798:Blood Proteins; D014859:Warfarin