title: Warfarin metabolites: stereochemical aspects of protein binding and displacement by phenylbutazone.
abstract: The in vitro human serum albumin binding characteristics of the enantiomers of the major metabolites of warfarin [6-hydroxywarfarin (6-HW), 7-hydroxywarfarin (7-HW), (S)-warfarin alcohols [(S,S)- and (S,R)-WA], and (R,S)-warfarin alcohol [(R,S)-WA]] have been studied, using a stereospecific HPLC assay. Warfarin metabolites are less bound both within plasma and a 40 g/liter solution of human serum albumin than the enantiomers of warfarin. The reduced warfarin metabolites have a lower fraction unbound [1.33% for (S,R)-WA, 2.09% for (S,S)-WA, and 1.04% for (R,S)-WA] than hydroxylated metabolites [3.24% for (R)-6-HW, 4.26% (S)-6-HW, 4.49% for (R)-7-HW and 4.27% for (S)-7-HW] to HSA. Phenylbutazone produced a concentration-dependent increase in the unbound fraction of all metabolites. It was possible to predict the unbound fraction of warfarin metabolites based on the unbound fraction of warfarin enantiomers.
authors.affiliation: Department of Pharmacy, University of Manchester, England.
authors.forename: E
authors.initials: E
authors.lastname: Chan
authors.forename: A J
authors.initials: AJ
authors.lastname: McLachlan
authors.forename: M
authors.initials: M
authors.lastname: Rowland
mesh_terms: D006801:Humans; D066298:In Vitro Techniques; D010653:Phenylbutazone / Q000378:metabolism*; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*; D013237:Stereoisomerism; D014859:Warfarin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D012709:Serum Albumin; D014859:Warfarin; D010653:Phenylbutazone