抗癫痫药物retigabine N-Glucuronidation:从研究结果与人类志愿者,不等的表达了人类与ugt,人类肝脏,肾脏,肝脏微粒体膜Crigler-Najjar II型。

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Borlak J, Gasparic,洛克M,写道H,赫尔曼·R

抗癫痫药物retigabine N-Glucuronidation:从研究结果与人类志愿者,不等的表达了人类与ugt,人类肝脏,肾脏,肝脏微粒体膜Crigler-Najjar II型。

新陈代谢。2006年6月,55岁(6):711 - 21所示。

PubMed ID

16713428 (在PubMed

]

文摘

Retigabine (d - 23129),一个N-2-amino-4——(4-fluorobenzylamino) phenylcarbamine酸乙酯,是一种新型的抗癫痫药物目前在二期临床的发展。这药经历N-glucuronidation。我们旨在识别的主要酶参与N-glucuronidation通路retigabine和比较我们的发现与那些来自人类的肝脏(30个捐助者的池)和肾微粒体(池3捐助者),结果从人类吸收,分布,代谢,排泄研究在政府200 microCi (14) C d - 23129。从本质上讲,微粒体化验UGT1A1仅2 N-glucuronides之一,而UGT1A9 N-glucuronides能够形成。UGT1A9新陈代谢的速度,人类肝微粒体和UGT1A1 200年,100年和100年pmol N-glucuronide每分钟每毫克的蛋白质,分别。在50 micromol / L尿苷二磷酸glucoronic酸(UDPGA)浓度,UGT1A4也催化retigabine N-glucuronidation,大约5和6的利率pmol /(最低。毫克的蛋白质)。UGT1A9,代谢物的生产1和2 K (m)进行38 + 45 + / / -25和-15 micromol / L,而K (m) retigabine N-glucuronidation由人类肝脏微粒体分数是145 + / -39 micromol / L。此外,V (max) 1.2 + / - -0.3 (nmol /分钟。毫克的蛋白质)估计人类肝脏微粒体(4个人捐助者)。我们调查潜在的药物之间交互使用抗癫痫药物丙戊酸,拉莫三嗪,三环类抗抑郁药丙咪嗪和麻醉药物异丙酚。 These are commonly used medications and are extensively glucuronidated. No potential for drug-drug interactions was found at clinically relevant concentrations (when assayed with human liver microsomes or UGT1A9 enzyme preparations). Notably, the biosynthesis of retigabine-N-glucuronides was not inhibited in human liver microsomal assays in the presence of 330 micromol/L bilirubin, and glucuronidation of retigabine was also observed with microsomal preparations from human kidney and Crigler-Najjar type II liver. This suggests that lack of a particular UDP-glucuronosyltransferase (UGT) isoform (eg, UGT1A1 in kidney) or functional loss of an entire UGT1A gene does not completely abolish disposal of the drug. Finally, chromatographic separations of extracts from microsomal assays and human urine of volunteers receiving a single dose of (14)C-retigabine provided clear evidence for the presence of the 2 N-glucuronides known to be produced by UGT1A9. We therefore suggest N-glucuronidation of retigabine to be of importance in the metabolic clearance of this drug.

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药物靶点

药物	目标	类	生物	药理作用	行动
Ezogabine	电压门控钾通道亚KQT成员4	蛋白质	人类	未知的	不可用	细节
Ezogabine	电压门控钾通道亚KQT成员5	蛋白质	人类	未知的	不可用	细节

药物酶

药物	酶	类	生物	药理作用	行动
Ezogabine	UDP-glucuronosyltransferase 1 - 1	蛋白质	人类	未知的	底物	细节