Metabolism and Pathways for Denitration of Organic Nitrates in the Human Liver
Metabolism and Pathways for Denitration of Organic Nitrates in the Human Liver
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DOI：
10.1124/jpet.113.203356
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发表时间：
2013-07-01
影响因子：
3.5
通讯作者：
Lundberg, Jon O.
中科院分区：
文献类型：
--
作者：
Govoni, Mirco;Tocchetti, Paola;Lundberg, Jon O.
肝脏首过代谢在不同的有机硝酸盐之间有很大的不同，但关于这些化合物在肝组织中的脱氮机制的信息很少。以自发代谢非依赖性一氧化氮(NO)供体[3-(aminopropyl)-1-hydroxy-3-isopropyl-2-oxo-1-triazene(NOC-5)为参照物，采用多种方法研究了氟比洛芬和阿魏酸的硝氧基丁酯在不同条件下的代谢，并与硝酸甘油进行了比较。硝氧基丁酯被快速、定量地代谢成它们各自的母体化合物和有机硝酸盐部分--硝基丁醇(NOBA)。与GTN快速、完全代谢为亚硝酸盐不同，NOBA被缓慢地代谢为硝酸盐。与自发的NO供体NOC-5相反，NOBA和GTN不产生可检测到的NO，也不能抑制细胞色素P450的活性，细胞色素P450是已知的被NO抑制的酶。肝脏代谢后NOBA的直接鉴定将该化合物作为硝酸丁酯的功能性有机硝酸盐代谢物。此外，对NOBA和GTN的脱氮途径的研究表明，有机硝酸盐在肝脏中不是主要代谢为NO，而是根据其不同的化学结构而产生不同程度的亚硝酸盐或硝酸盐。因此，口服有机硝酸盐不太可能影响辅佐药物的细胞色素P450依赖的代谢。然而，第一个过程可能会根据不同的反硝化程度和肝脏产生和输出的不同生物活性物种(硝酸盐或亚硝酸盐)而不同地影响有机硝酸盐的药理学特征。
Liver first-pass metabolism differs considerably among organic nitrates, but little information exists on the mechanism of denitration of these compounds in hepatic tissue. The metabolism of nitrooxybutyl-esters of flurbiprofen and ferulic-acid, a class of organic nitrates with potential therapeutic implication in variety of different conditions, was investigated in comparison with glyceryl trinitrate (GTN) in human liver by a multiple approach, using a spontaneous metabolism-independent nitric oxide (NO) donor [3-(aminopropyl)-1-hydroxy-3-isopropyl-2-oxo-1-triazene (NOC-5)] as a reference tool. Nitrooxybutyl-esters were rapidly and quantitatively metabolized to their respective parent compounds and the organic nitrate moiety nitrooxybutyl-alcohol (NOBA). Differently from GTN, which was rapidly and completely metabolized to nitrite, NOBA was slowly metabolized to nitrate. In contrast to the spontaneous NO donor NOC-5, NOBA and GTN did not generate detectable NO and failed to suppress the activity of cytochrome P450, an enzyme known to be inhibited by NO. The direct identification of NOBA after liver metabolism targets this compound as the functional organic nitrate metabolite of nitrooxybutyl-esters. Moreover, the investigation of the pathways for denitration of NOBA and GTN suggests that organic nitrates are not primarily metabolized to NO in the liver but to different extents of nitrite or nitrate depending in their different chemical structure. Therefore, cytochrome P450-dependent metabolism of concomitant drugs is not likely to be affected by oral coadministration of organic nitrates. However, the first pass may differently affect the pharmacological profile of organic nitrates in connection with the different extent of denitration and the distinct bioactive species generated and exported from the liver (nitrate or nitrite).