title: Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of posaconazole (Noxafil).
abstract: 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.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. anima.ghosal@spcorp.com
authors.forename: Anima
authors.initials: A
authors.lastname: Ghosal
authors.forename: Neil
authors.initials: N
authors.lastname: Hapangama
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.forename: Joana
authors.initials: J
authors.lastname: Achanfuo-Yeboah
authors.forename: Robert
authors.initials: R
authors.lastname: Iannucci
authors.forename: Swapan
authors.initials: S
authors.lastname: Chowdhury
authors.forename: Kevin
authors.initials: K
authors.lastname: Alton
authors.forename: James E
authors.initials: JE
authors.lastname: Patrick
authors.forename: Shmuel
authors.initials: S
authors.lastname: Zbaida
mesh_terms: D000935:Antifungal Agents / Q000378:metabolism*; D002853:Chromatography, Liquid; D003374:Coumarins / Q000378:metabolism; D020719:Glucuronides / Q000096:biosynthesis*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014230:Triazoles / Q000378:metabolism*; D014268:Trifluoperazine / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D003374:Coumarins; D020719:Glucuronides; D011994:Recombinant Proteins; D014230:Triazoles; C019787:bilirubin glucuronoside glucuronosyltransferase; D014268:Trifluoperazine; C084236:7-hydroxy-4-trifluoromethylcoumarin; C101425:posaconazole; D014453:Glucuronosyltransferase