title: Species-dependent enantioselective plasma protein binding of MK-571, a potent leukotriene D4 antagonist.
abstract: The plasma protein binding of the enantiomers of MK-571 was stereoselective and the stereoselectivity was species dependent. The 12 mammalian species studied could be classified into three groups: those that bind the S-(+)-enantiomer to a greater extent than the R-(-)-enantiomer (human, baboon, monkey, cow, dog, and cat); those that bind the R-(-)-enantiomer more extensively (rat, guinea pig, and sheep); and those that show no stereoselectivity (rabbit, hamster, and mouse). The stereoselective binding appears to have no phylogenetic relationship. Using serum albumin instead of plasma, a similar degree of stereoselective binding was observed for human, dog, sheep, and rat, suggesting that albumin is the major binding component for MK-571 enantiomers, and that species differences in stereoselective binding are likely due to structural differences in the albumin molecule. Displacement studies with [14C] diazepam, [14C]warfarin, and [3H]digitoxin indicated that the enantioselective differences in protein binding are most likely due to the differences in binding affinity rather than to different binding sites.
authors.affiliation: Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
authors.forename: J H
authors.initials: JH
authors.lastname: Lin
authors.forename: F A
authors.initials: FA
authors.lastname: deLuna
authors.forename: E H
authors.initials: EH
authors.lastname: Ulm
authors.forename: D J
authors.initials: DJ
authors.lastname: Tocco
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001798:Blood Proteins / Q000378:metabolism*; D002415:Cats; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D004074:Digitoxin / Q000493:pharmacokinetics; D004285:Dogs; D006168:Guinea Pigs; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D010215:Papio; D011422:Propionates / Q000097:blood* / Q000493:pharmacokinetics; D011804:Quinolines / Q000097:blood* / Q000493:pharmacokinetics; D011817:Rabbits; D051381:Rats; D013189:SRS-A / Q000037:antagonists & inhibitors*; D012709:Serum Albumin / Q000378:metabolism; D012756:Sheep; D013045:Species Specificity; D013237:Stereoisomerism; D014859:Warfarin / Q000493:pharmacokinetics
chemical_list: D001798:Blood Proteins; D011422:Propionates; D011804:Quinolines; D013189:SRS-A; D012709:Serum Albumin; D014859:Warfarin; C059141:verlukast; D004074:Digitoxin