TY - JOUR T1 - GLUCURONIDATION OF HMR1098 IN HUMAN MICROSOMES: EVIDENCE FOR THE INVOLVEMENT OF UGT1A1 IN THE FORMATION OF <em>S</em>-GLUCURONIDES JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1027 LP - 1034 DO - 10.1124/dmd.31.8.1027 VL - 31 IS - 8 AU - Brian T. Ethell AU - Jens Riedel AU - Heinrich Englert AU - Herbert Jantz AU - Raymond Oekonomopulos AU - Brian Burchell Y1 - 2003/08/01 UR - http://dmd.aspetjournals.org/content/31/8/1027.abstract N2 - 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 ER -