Metabolism and Excretion of the Novel Bioreductive Prodrug PR-104 in Mice, Rats, Dogs, and Humans
Metabolism and Excretion of the Novel Bioreductive Prodrug PR-104 in Mice, Rats, Dogs, and Humans
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DOI：
10.1124/dmd.109.030973
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发表时间：
2010-03-01
影响因子：
3.9
通讯作者：
Wilson, William R.
中科院分区：
文献类型：
--
作者：
Gu, Yongchuan;Atwell, Graham J.;Wilson, William R.
PR-104是3，5-二硝基苯甲酰胺氮芥（PR-104 A）的磷酸酯，其在肿瘤中被还原酶还原为活性羟胺和胺代谢物。在本研究中，我们评价了[H-3] PR-104在小鼠中的排泄，并确定了单次静脉给药后小鼠、大鼠、犬和人体中的代谢产物谱。总放射性在小鼠中快速定量排泄，尿液和粪便中的累积排泄率分别为46%和50%。小鼠中的主要尿液代谢产物为氮芥部分的氧化N-脱烷基化和/或谷胱甘肽结合产物，包括后续巯基尿酸途径代谢产物。在小鼠胆汁、小鼠血浆以及大鼠尿液和血浆中观察到相似的代谢产物谱。狗和人也表现出广泛的巯基结合，但几乎没有N -脱烷基化的证据。与啮齿类动物一样，人类血浆中的代谢物明显减少，但小鼠中细胞毒性胺代谢物（PR-104 M）的浓度高于人类。代谢产物谱中最显著的差异是犬和人中PR-104 A的O-β-葡萄糖醛酸化比啮齿动物中广泛得多。O-β-葡糖苷酸（PR 104 G）的结构通过独立合成得到证实。其尿液排泄占人体总剂量的13 +/- 2%，但在小鼠中仅占0.8 +/- 0.1%。基于这些代谢产物谱，PR-104在啮齿类动物中的生物转化与在人类中的生物转化显著不同，表明啮齿类动物可能不适合用于PR-104的人类生物转化和毒理学建模。
PR-104 is the phosphate ester of a 3,5-dinitrobenzamide nitrogen mustard (PR-104A) that is reduced to active hydroxylamine and amine metabolites by reductases in tumors. In this study, we evaluate the excretion of [H-3] PR-104 in mice and determine its metabolite profile in mice, rats, dogs, and humans after a single intravenous dose. Total radioactivity was rapidly and quantitatively excreted in mice, with cumulative excretion of 46% in urine and 50% in feces. The major urinary metabolites in mice were products from oxidative N-dealkylation and/or glutathione conjugation of the nitrogen mustard moiety, including subsequent mercapturic acid pathway metabolites. A similar metabolite profile was seen in mouse bile, mouse plasma, and rat urine and plasma. Dogs and humans also showed extensive thiol conjugation but little evidence of N -dealkylation. Humans, like rodents, showed appreciable reduced metabolites in plasma, but concentrations of the cytotoxic amine metabolite (PR-104M) were higher in mice than humans. The most conspicuous difference in metabolite profile was the much more extensive O-beta-glucuronidation of PR-104A in dogs and humans than in rodents. The structure of the O-beta-glucuronide (PR104G) was confirmed by independent synthesis. Its urinary excretion was responsible for 13 +/- 2% of total dose in humans but only 0.8 +/- 0.1% in mice. Based on these metabolite profiles, biotransformation of PR-104 in rodents is markedly different from that in humans, suggesting that rodents may not be appropriate for modeling human biotransformation and toxicology of PR-104.