Warfarin and UDP-glucuronosyltransferases: writing a new chapter of metabolism

The widely prescribed anticoagulant, Coumadin (racemic R/S-warfarin), Bristol-Myers Squibb Company, Clinton, NY has a narrow therapeutic range and wide interindividual response due, in part, to drug metabolism. Early identification of hydroxywarfarins (OHWARs), especially S-7-OHWAR, as major metabolites fostered studies characterizing cytochrome P450s responsible for those reactions. Nevertheless, phase II metabolism by sulfotransferases and, -especially uridine diphosphate (UDP)-glucuronosyltransferases (UGTs), marks the next chapter in warfarin inactivation and clearance. Rodents converted OHWARs to glucuronides (O-GLUC), including high levels of 4'-, 7-, and 8-O-GLUC. Similarly, humans generated significant levels of glucuronides following treatment with warfarin. 7-O-GLUC was a major metabolite, while 6- and 8-O-GLUC were minor ones. Surprisingly, warfarin glucuronidation accounted for up to 13% of metabolites. This capacity in humans derives from several UGTs, as shown by studies with recombinant enzymes and racemic warfarin and OHWARs. 7-OHWAR was a high-affinity substrate for UGT1A1, compared to other UGTs. UGT1A1 and UGT1A10 also glucuronidated 6-OHWAR. Of five UGT1A enzymes, UGT1A10 was approximately 7-fold more efficient than the rest. Broad substrate specificity for UGT1A10 derives, in part, from an active site-binding motif, specifically F