识别的N-methyl-4-phenylpyridinium-like代谢物止泻剂剂洛派丁胺在人类肝微粒体:根本原因(年代)缺乏神经毒性,尽管bioactivation事件。
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Kalgutkar,阮HT
识别的N-methyl-4-phenylpyridinium-like代谢物止泻剂剂洛派丁胺在人类肝微粒体:根本原因(年代)缺乏神经毒性,尽管bioactivation事件。
药物金属底座Dispos。2004年9月,32 (9):943 - 52。
- PubMed ID
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15319335 (在PubMed]
- 文摘
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它们在与帕金森效果与线粒体有关的神经毒素N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine注射(MPTP药物)和神经松弛剂氟哌啶醇,存在没有报告不良中枢神经系统(CNS)效应与结构相关N-substituted-4-arylpiperidin-4-ol导数和止泻的代理洛派丁胺。尽管这种差异可以归因于洛派丁胺的22衬底属性,防止它进入大脑,另一种可能性是,洛派丁胺代谢在人类不同于注射的MPTP药物和氟哌啶醇,不涉及bioactivation毒害神经的吡啶的物种。在最近的研究中,洛派丁胺bioactivation与重点研究吡啶代谢物的识别。观察NADPH-dependent失踪的洛派丁胺在老鼠和人类肝脏微粒体(人类t(1/2) = 13分钟;鼠t(1/2) = 22分钟)。洛派丁胺代谢相似人类和老鼠和N-dealkylation N-desmethylloperamide (M3)的主要代谢的命运。其他航线的洛派丁胺生物转化包括N -和C-hydroxylation loperamide-N-oxide (M4)和carbinolamide (M2)代谢产物,分别。此外,额外的形成代谢物(M5)也明显在人类和大鼠肝微粒体。M5被分配到吡啶物种的结构(垂直距离(+))基于比较的液相色谱/串联质谱特征的吡啶从洛派丁胺通过化学反应。洛派丁胺代谢对酮康唑和安非他酮治疗人类微粒体敏感,表明P4503A4和2 b6参与。 Recombinant P4503A4 catalyzed all of the loperamide biotransformation pathways in human liver microsomes, whereas P4502B6 was only responsible for N-dealkylation and N-oxidation routes. The wide safety margin of loperamide (compared with MPTP and haloperidol) despite metabolism to a potentially neurotoxic pyridinium species likely stems from a combination of factors that include a therapeutic regimen normally restricted to a few days and the fact that loperamide and perhaps LPP(+) are P-glycoprotein substrates and are denied entry into the CNS. The differences in safety profile of haloperidol and loperamide despite a common bioactivation event supports the notion that not all compounds undergoing bioactivation in vitro will necessarily elicit a toxicological response in vivo.
