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Jones DR, Moran JH, Miller GP: Warfarin and UDP-glucuronosyltransferases: writing a new chapter of metabolism. Drug Metab Rev. 2010;42(1):53-9.
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 F90-M91-V92-F93. Unlike glucuronidation, less is known about sulfonation of warfarin and its metabolites, except that low capacities are shown by rats and, possibly, humans. Collectively, phase I and II metabolic steps create pathways for inactivating and eliminating warfarin that require elucidation. These findings will ultimately enrich our understanding of warfarin metabolism and facilitate the interpreting of metabolic profiles of patients. This knowledge will possibly avoid complications during warfarin therapy related to metabolism by personalizing therapy for the patient. |
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