RT Journal Article
SR Electronic
T1 IDENTIFICATION OF HUMAN UDP-GLUCURONOSYLTRANSFERASE ENZYME(S) RESPONSIBLE FOR THE GLUCURONIDATION OF POSACONAZOLE (NOXAFIL)
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 267
OP 271
DO 10.1124/dmd.32.2.267
VO 32
IS 2
A1 Anima Ghosal
A1 Neil Hapangama
A1 Yuan Yuan
A1 Joana Achanfuo-Yeboah
A1 Robert Iannucci
A1 Swapan Chowdhury
A1 Kevin Alton
A1 James E. Patrick
A1 Shmuel Zbaida
YR 2004
UL http://dmd.aspetjournals.org/content/32/2/267.abstract
AB 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