title: Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of 3-hydroxydesloratadine.
abstract: Desloratadine is a non-sedating antihistamine recently approved for the treatment of seasonal allergic rhinitis. The major metabolite of desloratadine in human plasma and urine is the glucuronide conjugate of 3-hydroxydesloratadine. 3-Hydroxydesloratadine-glucuronide is also the major in vitro metabolite of 3-hydroxydesloratadine formed by incubation of 3-hydroxydesloratadine with human liver microsomes supplemented with uridine 5'-diphosphate-glucuronic acid (UDPGA). The metabolite structure was confirmed by LC-MS and LC-MS/MS. Out of ten recombinant human UDP-glucuronosyltransferases (UGTs), UGT1A1, UGT1A3, UGT1A8 and UGT2B15 exhibited catalytic activity with respect to the formation of 3-hydroxydesloratadine-glucuronide. Inhibition studies with known inhibitors of UGT (diclofenac, flunitrazepam and bilirubin) confirmed the involvement of UGT1A1, UGT1A3 and UGT2B15 in the formation of 3-hydroxydesloratadine-glucuronide. The results from this study demonstrated that the in vitro formation of 3-hydroxydesloratadine-glucuronide from 3-hydroxydesloratadine was mediated via UGT1A1, UGT1A3 and UGT2B15 in human liver.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. anima.ghosal@spcorp.com
authors.forename: Anima
authors.initials: A
authors.lastname: Ghosal
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.forename: Neil
authors.initials: N
authors.lastname: Hapangama
authors.forename: Ai Duen Iris
authors.initials: AD
authors.lastname: Su
authors.forename: Narciso
authors.initials: N
authors.lastname: Alvarez
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Chowdhury
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Alton
authors.forename: James E
authors.initials: JE
authors.lastname: Patrick
authors.forename: Shmuel
authors.initials: S
authors.lastname: Zbaida
mesh_terms: D001663:Bilirubin / Q000494:pharmacology; D004008:Diclofenac / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005445:Flunitrazepam / Q000494:pharmacology; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism*; D039563:Histamine H1 Antagonists, Non-Sedating / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D017336:Loratadine / Q000031:analogs & derivatives* / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D013997:Time Factors; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D004008:Diclofenac; D004791:Enzyme Inhibitors; D005445:Flunitrazepam; D020719:Glucuronides; D014453:Glucuronosyltransferase; D039563:Histamine H1 Antagonists, Non-Sedating; D017336:Loratadine; D000099148:UGT1A1 Enzyme; C482880:3-hydroxydesloratadine; C122075:UDP-glucuronosyltransferase, UGT1A3; C472000:UDP-glucuronosyltransferase 2B15, human; C454320:UDP-glucuronosyltransferase, UGT1A8; C121345:desloratadine