Identification of circulatory and excretory metabolites of a novel nitric oxide donor ZJM-289 in rat plasma, bile, urine and faeces by liquid chromatography–tandem mass spectrometry
Identification of circulatory and excretory metabolites of a novel nitric oxide donor ZJM-289 in rat plasma, bile, urine and faeces by liquid chromatography–tandem mass spectrometry
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DOI：
10.3109/00498254.2011.580385
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发表时间：
2011-08
期刊：
影响因子：
1.8
通讯作者：
Ning Li;Xuliang Wang;Ting-ting Li;H. Ji;Yihua Zhang;Zhixia Qiu;Di Zhao;Xijing Chen
中科院分区：
文献类型：
--
作者：
Ning Li;Xuliang Wang;Ting-ting Li;H. Ji;Yihua Zhang;Zhixia Qiu;Di Zhao;Xijing Chen
ZJM-289，[2-(1-二乙氨基乙酰氧基)戊基]苯甲酸-{2-甲氧基-4-[2-(4-硝氧基丁氧基)-乙烯基]}苯酯盐酸盐，是一种新型的3-正丁基苯酞的一氧化氮供体衍生物，假设它在体内可能被水解成3-正丁基苯酞、阿魏酸和一氧化氮，希望这三种成分对血小板和中枢神经系统产生协同作用。在本研究中，ZJM-289在大鼠体内被广泛代谢。大鼠静脉给药后血浆、胆汁、尿液和粪便中的8种主要代谢物经LC-MS/MS鉴定。代谢产物M1、M2、M3、M4和M5是ZJM-289的水解物，M6和M7是M5的羟基化产物，M8是M1的葡萄糖醛酸苷。药理活性代谢物阿魏酸(M3)是所有生物基质中的主要代谢物。3-正丁基苯酞在血液循环中也处于中等水平。与以往的研究结果表明，ZJM-289在体内和体外的抗血小板活性均强于3-正丁基苯酞。所有这些发现都验证了药物设计理论。
ZJM-289, [2-(1-diethylaminoacetoxy)pentyl] benzoic acid-{2-methoxy-4-[2-(4-nitrooxybutoxy carbonyl)-vinyl]}phenyl ester hydrochloride, is a novel nitric oxide–donating derivative of 3-n-butylphthalide synthesised on the hypothesis that it may be hydrolysed in vivo into 3-n-butylphthalide, ferulic acid and nitric oxide in hope that the three components may exert effects on the platelets as well as on central nervous system synergistically. In this study, ZJM-289 was extensively metabolised in rats. Eight major metabolites were identified by liquid chromatography (LC)–mass spectrometry (MS)/MS in rat plasma, bile, urine and faeces after intravenous administration. Metabolites M1, M2, M3, M4 and M5 were hydrolytic products of ZJM-289, M6 and M7 was a hydroxylation product of M5, and M8 was a glucuronide of M1. The pharmacologically active metabolite ferulic acid (M3) was a major metabolite in all the biological matrixes examined. 3-n-Butylphthalide was also present at a moderate level in the circulation. And along with the previous research, the anti-platelet activity of ZJM-289 was more potent than that of 3-n-butylphthalide both in vivo and in vitro. All these findings validated the theory of drug design.