In vitro and in vivo metabolism of N-adamantyl substituted urea-based soluble epoxide hydrolase inhibitors.
In vitro and in vivo metabolism of N-adamantyl substituted urea-based soluble epoxide hydrolase inhibitors.
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N-金刚烷基取代脲基可溶性环氧化物水解酶抑制剂的体外和体内代谢
DOI：
10.1016/j.bcp.2015.10.013
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发表时间：
2015-12-15
影响因子：
5.8
通讯作者：
Hammock BD
中科院分区：
文献类型：
--
作者：
Liu JY;Tsai HJ;Morisseau C;Lango J;Hwang SH;Watanabe T;Kim IH;Hammock BD
N，N‘-二取代基于尿素的可溶性环氧化物水解酶(SEH)抑制剂是治疗多种动物模型高血压、炎症和疼痛的有前途的药物。这些抑制剂的药物吸收和药理作用已被广泛报道。然而，这些抑制剂的药物代谢还没有得到很好的描述。在此，我们报道了一种基于N-金刚烷基脲的sEH抑制剂1-adamantan-1-yl-3-(5-(2-(2-ethoxyethoxy)ethoxy)pentyl)urea(AEPU)的体内外代谢情况和相关的生化研究。采用液-质联用(LC-MS)、液-质联用(LC-MS/MS)和/或核磁共振对AEPU的代谢产物进行了鉴定。在体外，AEPU有三个主要的I相代谢部位，包括金刚烷基上的氧化、尿素氮原子和聚乙二醇链的断裂。在啮齿动物模型中，血液中存在金刚烷基和氮原子上羟基化的代谢物，而尿中未发现聚乙二醇链断裂的代谢物。在啮齿动物尿液中发现的主要代谢物是3-(3-金刚烷基脲)丙酸，这是一种可能来自聚乙二醇基的裂解和氧化。所有发现的代谢物都是活性的，但在抑制人sEH方面不如AEPU。此外，细胞色素P450(CYP)3A4是AEPU代谢的主要调节酶。综上所述，AEPU在CYP氧化作用下的代谢可以与其他N-金刚烷基脲类化合物共享。这些发现提示了AEPU可能的治疗作用和这一系列可能药物的药物设计的新策略。
N,N′-Disubstituted urea-based soluble epoxide hydrolase (sEH) inhibitors are promising therapeutics for hypertension, inflammation, and pain in multiple animal models. The drug absorption and pharmacological efficacy of these inhibitors have been reported extensively. However, the drug metabolism of these inhibitors is not well described. Here we reported the metabolic profile and associated biochemical studies of an N-adamantyl urea-based sEH inhibitor 1-adamantan-1-yl-3-(5-(2-(2-ethoxyethoxy)ethoxy)pentyl)urea (AEPU) in vitro and in vivo. The metabolites of AEPU were identified by interpretation of liquid chromatography-mass chromatography (LC-MS), liquid chromatography-tandem mass spectrometry (LC-MS/MS) and/or NMR. In vitro, AEPU had three major positions for phase I metabolism including oxidations on the adamantyl moiety, urea nitrogen atoms, and cleavage of the polyethylene glycol chain. In a rodent model, the metabolites from the hydroxylation on the adamantyl group and nitrogen atom were existed in blood while the metabolites from cleavage of polyethylene glycol chain were not found in urine. The major metabolite found in rodent urine was 3-(3-adamantyl-ureido)-propanoic acid, a presumably from cleavage and oxidation of the polyethylene glycol moiety. All the metabolites found were active but less potent than AEPU at inhibiting human sEH. Furthermore, cytochrome P450 (CYP) 3A4 was found to be a major enzyme mediating AEPU metabolism. In conclusion, the metabolism of AEPU resulted from oxidation by CYP could be shared with other N-adamantyl-urea-based compounds. These findings suggest possible therapeutic roles for AEPU and new strategies for drug design in this series of possible drugs.