WARFARIN METABOLITES - STEREOCHEMICAL ASPECTS OF PROTEIN-BINDING AND DISPLACEMENT BY PHENYLBUTAZONE

The in vitro human serum albumin binding characteristics of the enanti omers 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 ste reospecific HPLC assay. Warfarin metabolites are less bound both withi n plasma and a 40 g/liter solution of human serum albumin than the ena ntiomers of warfarin. The reduced warfarin metabolites have a lower fr action unbound [1. 33% for (S, R)-WA, 2.09% for (S,S)-WA, and 1.04% fo r (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. Phenylbuta zone produced a concentration-dependent increase in the unbound fracti on of an metabolites. It was possible to predict the unbound fraction of warfarin metabolites based on the unbound fraction of warfarin enan tiomers.