Glucuronidation的他汀类药物在动物和人类:小说他汀类内酯化机理。

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方Prueksaritanont T,萨勃拉曼尼亚R, X,马B,邱Y,林JH,皮尔森PG,柏丽助教

Glucuronidation的他汀类药物在动物和人类:小说他汀类内酯化机理。

药物金属底座Dispos。2002; 30 (5): 505 - 12。

PubMed ID

11950779 (在PubMed

]

文摘

活动形式的所有销售hydroxymethylglutaryl辅酶a还原酶抑制剂(HMG)共享一个共同的二羟基庚庚烯酸侧链。在这项研究中,我们提出证据的形成酰基葡糖苷酸羟基酸的轭合物形式的辛伐他汀(上海广电),阿托伐他汀(瓦),和cerivastatin (CVA)老鼠,狗和人类肝脏制剂体外和上海广电的酰基葡糖苷酸的排泄狗胆汁和尿液。在孵化的他汀类药物(上海广电、脑血管意外或艾娃)与肝微粒体准备补充UDP-glucuronic酸,发现了两个主要的产品。基于分析高压液相色谱,紫外光谱,和/或液相色谱质谱法(LC)分析,这些代谢物被确认为一种葡糖苷酸羟基酸的共轭形式的他汀类和相应的delta-lactone。通过一个LC-NMR技术,建立了葡糖苷酸结构是1-O-acyl-beta-D-glucuronide共轭酸的他汀类药物。他汀类葡糖苷酸的形成和他汀内酯在人类肝微粒体表现出适度的主体间变异性(3 - 6倍;n = 10)。研究表示UDP glucuronosyltransferases (ugt)透露,UGT1A1和UGT1A3都能够形成葡糖苷酸配合和相应的内酯为所有三个他汀类药物。动力学研究他汀类glucuronidation和内酯化的肝微粒体显示明显的物种差异内在间隙(CL (int))值为上海广电(但不是艾娃,患者,CL (int)中观察到的最高的狗,老鼠和人类紧随其后。他汀类药物的研究,上海广电接受glucuronidation人类肝微粒体和内酯化,最低的CL (int) (0.4 microl /分钟/毫克的蛋白质为上海广电和大约3 microl /分钟/毫克的蛋白质艾娃和脑血管意外)。 Consistent with the present in vitro findings, substantial levels of the glucuronide conjugate (approximately 20% of dose) and the lactone form of SVA [simvastatin (SV); approximately 10% of dose] were detected in bile following i.v. administration of [(14)C]SVA to dogs. The acyl glucuronide conjugate of SVA, upon isolation from an in vitro incubation, underwent spontaneous cyclization to SV. Since the rate of this lactonization was high under conditions of physiological pH, the present results suggest that the statin lactones detected previously in bile and/or plasma following administration of SVA to animals or of AVA or CVA to animals and humans, might originate, at least in part, from the corresponding acyl glucuronide conjugates. Thus, acyl glucuronide formation, which seems to be a common metabolic pathway for the hydroxy acid forms of statins, may play an important, albeit previously unrecognized, role in the conversion of active HMG-CoA reductase inhibitors to their latent delta-lactone forms.

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药物酶

药物	酶	类	生物	药理作用	行动
洛伐他汀	UDP-glucuronosyltransferase 2 b7	蛋白质	人类	未知的	底物	细节