Ghosal Anima, Yuan Yuan, Hapangama Neil, Su Ai Duen Iris, Alvarez Narciso, Chowdhury Swapan K, Alton Kevin B, Patrick James E, Zbaida Shmuel
Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
Biopharm Drug Dispos. 2004 Sep;25(6):243-52. doi: 10.1002/bdd.405.
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.
地氯雷他定是一种新型非镇静性抗组胺药，最近被批准用于治疗季节性变应性鼻炎。地氯雷他定在人血浆和尿液中的主要代谢产物是3-羟基地氯雷他定的葡糖醛酸结合物。3-羟基地氯雷他定葡糖醛酸结合物也是3-羟基地氯雷他定与人肝微粒体及尿苷5'-二磷酸葡糖醛酸（UDPGA）孵育形成的主要体外代谢产物。代谢产物结构经液相色谱-质谱（LC-MS）和液相色谱-串联质谱（LC-MS/MS）确证。在10种重组人尿苷二磷酸葡糖醛酸基转移酶（UGT）中，UGT1A1、UGT1A3、UGT1A8和UGT2B15对3-羟基地氯雷他定葡糖醛酸结合物形成表现出催化活性；用已知UGT抑制剂（双氯芬酸、氟硝西泮和胆红素）进行的抑制研究证实UGT1A1、UGT1A3及UGT2B15参与了3-羟基地氯雷他定葡糖醛酸结合物的形成。本研究结果表明，人肝中的UGT1A1、UGT1A3和UGT2B15介导了3-羟基地氯雷他定在体外形成3-羟基地氯雷他定葡糖醛酸结合物的过程。
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