RT Journal Article SR Electronic T1 GLUCURONIDATION OF HMR1098 IN HUMAN MICROSOMES: EVIDENCE FOR THE INVOLVEMENT OF UGT1A1 IN THE FORMATION OF S-GLUCURONIDES JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1027 OP 1034 DO 10.1124/dmd.31.8.1027 VO 31 IS 8 A1 Brian T. Ethell A1 Jens Riedel A1 Heinrich Englert A1 Herbert Jantz A1 Raymond Oekonomopulos A1 Brian Burchell YR 2003 UL http://dmd.aspetjournals.org/content/31/8/1027.abstract AB HMR1098, a novel KATP-blocking agent, is metabolized to form an S-glucuronide in rat and dog bile. Synthesis of the S-glucuronide metabolite was studied in human liver and kidney microsomes. Recombinant UPD-glucuronosyltransferases (UGTs) were screened for activity, and kinetic analysis was performed to identify the isoform or isoforms responsible for the formation of this novel S-glucuronide in humans. S-Glucuronidation is relatively rare, but from this study it appears that S-glucuronides are not generated exclusively by a single UGT isoform. From the panel of recombinant isoforms used, both UGT1A1 and UGT1A9 catalyzed the glucuronidation of HMR1098. The Vmax values in both instances were similar, but the Km for UGT1A1 was substantially lower than that measured for UGT1A9, 82 μM compared with 233 μM, respectively. Liver and kidney microsomes displayed similar Km values, but the Vmax in kidney was more than 20-fold less than in liver microsomes, which is suggestive of a significant role for the bilirubin UGT in catalysis of HMR1098, although other UGTs may play a secondary role. The American Society for Pharmacology and Experimental Therapeutics