Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of 3-hydroxydesloratadine. 2004

Anima Ghosal, and Yuan Yuan, and Neil Hapangama, and Ai Duen Iris Su, and Narciso Alvarez, and Swapan K Chowdhury, and Kevin B Alton, and James E Patrick, and Shmuel Zbaida
Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. anima.ghosal@spcorp.com

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.

UI MeSH Term Description Entries
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D004008 Diclofenac A non-steroidal anti-inflammatory agent (NSAID) with antipyretic and analgesic actions. It is primarily available as the sodium salt. Diclophenac,Dichlofenal,Diclofenac Potassium,Diclofenac Sodium,Diclonate P,Dicrofenac,Feloran,GP-45,840,Novapirina,Orthofen,Orthophen,Ortofen,SR-38,Sodium Diclofenac,Voltaren,Voltarol,Diclofenac, Sodium,GP 45,840,GP45,840,SR 38,SR38
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D005445 Flunitrazepam A benzodiazepine with pharmacologic actions similar to those of DIAZEPAM that can cause ANTEROGRADE AMNESIA. Some reports indicate that it is used as a date rape drug and suggest that it may precipitate violent behavior. The United States Government has banned the importation of this drug. Fluridrazepam,Rohypnol,Fluni 1A Pharma,Flunibeta,Flunimerck,Fluninoc,Flunitrazepam-Neuraxpharm,Flunitrazepam-Ratiopharm,Flunitrazepam-Teva,Flunizep Von Ct,Narcozep,RO-5-4200,Rohipnol,Flunitrazepam Neuraxpharm,Flunitrazepam Ratiopharm,Flunitrazepam Teva,RO54200,Von Ct, Flunizep
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001663 Bilirubin A bile pigment that is a degradation product of HEME. Bilirubin IX alpha,Bilirubin, (15E)-Isomer,Bilirubin, (4E)-Isomer,Bilirubin, (4E,15E)-Isomer,Bilirubin, Calcium Salt,Bilirubin, Disodium Salt,Bilirubin, Monosodium Salt,Calcium Bilirubinate,Hematoidin,delta-Bilirubin,Bilirubinate, Calcium,Calcium Salt Bilirubin,Disodium Salt Bilirubin,Monosodium Salt Bilirubin,Salt Bilirubin, Calcium,delta Bilirubin
D013997 Time Factors Elements of limited time intervals, contributing to particular results or situations. Time Series,Factor, Time,Time Factor
D014453 Glucuronosyltransferase A family of enzymes accepting a wide range of substrates, including phenols, alcohols, amines, and fatty acids. They function as drug-metabolizing enzymes that catalyze the conjugation of UDPglucuronic acid to a variety of endogenous and exogenous compounds. EC 2.4.1.17. Glucuronyltransferase,UDP Glucuronosyltransferase,17 beta-Hydroxysteroid UDP-Glucuronosyltransferase,4-Nitrophenol-UDP-Glucuronosyltransferase,7-Hydroxycoumarin UDP Glucuronyltransferase,Androsterone UDP-Glucuronosyltransferase,Bilirubin UDP-Glucuronyltransferase,Estrogen UDP-Glucuronosyltransferase,Estrone Glucuronyltransferase,Glucuronic Transferase,Morphine Glucuronyltransferase,UDP Glucuronyl Transferase,UDP-Glucuronic Acid 3-O-beta-D-Galactosyl-D-Galactose Glucuronosyltransferase,p-Nitrophenyl UDP-Glucuronosyltransferase,17 beta Hydroxysteroid UDP Glucuronosyltransferase,4 Nitrophenol UDP Glucuronosyltransferase,7 Hydroxycoumarin UDP Glucuronyltransferase,Androsterone UDP Glucuronosyltransferase,Bilirubin UDP Glucuronyltransferase,Estrogen UDP Glucuronosyltransferase,Glucuronosyltransferase, UDP,Glucuronyl Transferase, UDP,Glucuronyltransferase, 7-Hydroxycoumarin UDP,Glucuronyltransferase, Estrone,Glucuronyltransferase, Morphine,Transferase, Glucuronic,Transferase, UDP Glucuronyl,UDP Glucuronic Acid 3 O beta D Galactosyl D Galactose Glucuronosyltransferase,UDP Glucuronyltransferase, 7-Hydroxycoumarin,UDP-Glucuronosyltransferase, 17 beta-Hydroxysteroid,UDP-Glucuronosyltransferase, Androsterone,UDP-Glucuronosyltransferase, Estrogen,UDP-Glucuronosyltransferase, p-Nitrophenyl,UDP-Glucuronyltransferase, Bilirubin,p Nitrophenyl UDP Glucuronosyltransferase
D017336 Loratadine A second-generation histamine H1 receptor antagonist used in the treatment of allergic rhinitis and urticaria. Unlike most classical antihistamines (HISTAMINE H1 ANTAGONISTS) it lacks central nervous system depressing effects such as drowsiness. 4-(8-Chloro-5,6-dihydro-11H-benzo(5,6)cyclohepta(1,2-b)pyridin-11-ylidene)-1-piperidinecarboxylic Acid Ethyl Ester,Alavert,Claritin,Clarium,Sch-29851,Sch 29851,Sch29851
D020719 Glucuronides Glycosides of GLUCURONIC ACID formed by the reaction of URIDINE DIPHOSPHATE GLUCURONIC ACID with certain endogenous and exogenous substances. Their formation is important for the detoxification of drugs, steroid excretion and BILIRUBIN metabolism to a more water-soluble compound that can be eliminated in the URINE and BILE. Glucuronide

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