Department of Physiology and Pharmacology, Karolinska Institute, Nanna Svartz väg 2, S-177 76 Stockholm, Sweden.
J Pharmacol Exp Ther. 2013 Jul;346(1):96-104. doi: 10.1124/jpet.113.203356. Epub 2013 Apr 17.
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).
肝脏的首过代谢在不同的有机硝酸盐之间有很大的差异，但关于这些化合物在肝组织中脱硝的机制知之甚少。本研究采用多种方法，以一种自发代谢无关的一氧化氮（NO）供体[3-(氨基丙基)-1-羟基-3-异丙基-2-氧代-1-三嗪（NOC-5）]作为参考工具，比较了氟比洛芬和阿魏酸的硝基氧丁酯（一种在多种不同情况下具有潜在治疗意义的有机硝酸盐类）与甘油三硝酸酯（GTN）在人肝中的代谢情况。硝基氧丁酯迅速且定量地代谢为各自的母体化合物和有机硝酸盐部分硝基氧丁醇（NOBA）。与迅速且完全代谢为亚硝酸盐的 GTN 不同，NOBA 缓慢代谢为硝酸盐。与自发的 NO 供体 NOC-5 不同，NOBA 和 GTN 不能检测到 NO 的产生，也不能抑制细胞色素 P450 的活性，已知细胞色素 P450 被 NO 抑制。肝代谢后直接鉴定出的 NOBA 将其靶向为硝基氧丁酯的功能性有机硝酸盐代谢物。此外，对 NOBA 和 GTN 脱硝途径的研究表明，有机硝酸盐在肝脏中并非主要代谢为 NO，而是根据其不同的化学结构，不同程度地代谢为亚硝酸盐或硝酸盐。因此，细胞色素 P450 依赖性代谢的伴随药物不太可能受到口服同时给予有机硝酸盐的影响。然而，首过效应可能会因脱硝程度的不同以及从肝脏中生成和输出的不同活性物质（硝酸盐或亚硝酸盐）而对有机硝酸盐的药理学特征产生不同的影响。
