%0 Journal Article %A Shinsuke Uchihashi %A Hiroyuki Fukumoto %A Makoto Onoda %A Hiroyoshi Hayakawa %A Shin-ichi Ikushiro %A Toshiyuki Sakaki %T Metabolism of the c-Fos/activator protein-1 inhibitor T-5224 by multiple human UGT isoforms %D 2011 %R 10.1124/dmd.110.037952 %J Drug Metabolism and Disposition %P dmd.110.037952 %X We developed T-5224 as a novel inhibitor of the c-Fos/activator protein-1 for rheumatoid arthritis therapy. We predicted the metabolism of T-5224 in humans by using human liver microsomes (HLMs), human intestinal microsomes (HIMs), recombinant human cytochrome P450 (P450) and UDP-glucuronosyltransferases (UGTs). T-5224 was converted to its acyl O-glucuronide (G2) by UGT1A1 and UGT1A3 and to its hydroxyl O-glucuronide (G3) by several UGTs, but it was not metabolized by the P450s. Comparing the intrinsic clearances (CLint) between HLM and HIM suggested that the glucuronidation of T-5224 predominantly occurs in the liver. UGT1A1 showed a higher kcat/Km value compared to UGT1A3 for the G2 formation but a lower kcat/Km value compared to UGT1A3 for G3 formation. A high correlation was observed between G2 formation activity and UGT1A1-specific activity (β-estradiol 3-glucuronidation) in 7 individual HLMs. A high correlation was also observed between G2 formation activity and UGT1A1 content in the HLMs. These results strongly suggest that UGT1A1 is responsible for the G2 formation in the human liver. In contrast, no such correlation was observed with G3 formation, suggesting that multiple UGT isoforms, including UGT1A1 and UGT1A3, are involved in the G3 formation. G2 is also observed in rat and monkey liver microsomes as a major metabolite of T-5224, suggesting that G2 is not a human-specific metabolite. In this study, we obtained useful information on the metabolism of T-5224 for its clinical use. %U https://dmd.aspetjournals.org/content/dmd/early/2011/02/23/dmd.110.037952.full.pdf