TY - JOUR T1 - IDENTIFICATION OF HUMAN UDP-GLUCURONOSYLTRANSFERASE ENZYME(S) RESPONSIBLE FOR THE GLUCURONIDATION OF POSACONAZOLE (NOXAFIL) JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 267 LP - 271 DO - 10.1124/dmd.32.2.267 VL - 32 IS - 2 AU - Anima Ghosal AU - Neil Hapangama AU - Yuan Yuan AU - Joana Achanfuo-Yeboah AU - Robert Iannucci AU - Swapan Chowdhury AU - Kevin Alton AU - James E. Patrick AU - Shmuel Zbaida Y1 - 2004/02/01 UR - http://dmd.aspetjournals.org/content/32/2/267.abstract N2 - Posaconazole (Noxafil, SCH 56592), an orally available broad-spectrum triazole antifungal, is currently in phase III clinical studies for treating serious opportunistic fungal infections. The major in vitro metabolite of posaconazole formed by human liver microsomes supplemented with uridine 5′-diphosphate-glucuronic acid was a glucuronide of posaconazole (m/z877). Screening of 10 cDNA-expressed recombinant human UDP-glucuronosyltransferase (UGT) enzymes showed that only UGT1A4 exhibited catalytic activity with respect to the formation of the glucuronide of posaconazole. The formation of glucuronide by human liver microsomes and UGT1A4 was inhibited by bilirubin, a known inhibitor of UGT1A4. There was a high correlation (r =0.90) between the rate of formation of glucuronide, determined in 10 human liver microsomal samples, and trifluoperazine glucuronidation catalyzed by UGT1A4. These results confirmed that the formation of major posaconazole-glucuronide produced from human liver microsomes was mediated via UGT1A4. The American Society for Pharmacology and Experimental Therapeutics ER -