Ghosal Anima, Hapangama Neil, Yuan Yuan, Achanfuo-Yeboah Joana, Iannucci Robert, Chowdhury Swapan, Alton Kevin, Patrick James E, Zbaida Shmuel
Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Drug Metab Dispos. 2004 Feb;32(2):267-71. doi: 10.1124/dmd.32.2.267.
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.
泊沙康唑（诺科飞，SCH 56592）是一种口服的广谱三唑类抗真菌药，目前正处于治疗严重机会性真菌感染的III期临床研究阶段。在添加尿苷5'-二磷酸葡萄糖醛酸的人肝微粒体中形成的泊沙康唑主要体外代谢产物是泊沙康唑的葡萄糖醛酸苷（m/z877）。对10种cDNA表达的重组人尿苷二磷酸葡萄糖醛酸基转移酶（UGT）进行筛选，结果表明只有UGT1A4对泊沙康唑葡萄糖醛酸苷的形成具有催化活性。人肝微粒体和UGT1A4形成葡萄糖醛酸苷的过程受到胆红素（一种已知的UGT1A4抑制剂）的抑制。在10个人肝微粒体样品中测定的葡萄糖醛酸苷形成速率与UGT1A4催化的三氟拉嗪葡萄糖醛酸化之间存在高度相关性（r = 0.90）。这些结果证实，人肝微粒体产生的主要泊沙康唑葡萄糖醛酸苷的形成是通过UGT1A4介导的。
