羧酸酯酶1和2参与霉酚酸酯的水解。
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富士山N,三浦M,加藤,宋T, Isobe M, Satoh年代
羧酸酯酶1和2参与霉酚酸酯的水解。
药物金属底座Dispos。2010年12月,38 (12):2210 - 7。doi: 10.1124 / dmd.110.034249。Epub 2010年9月7日。
- PubMed ID
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20823294 (在PubMed]
- 文摘
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霉酚酸酯(MMF)酯前体药物的免疫抑制剂剂霉酚酸(MPA),口服后迅速由酯酶激活。然而,在MMF同功酶水解的作用尚不清楚。虽然人血浆、红细胞和全血包含MMF水解活动,MMF体外的平均半衰期分别为15.1,1.58,和3.20 h,分别。因此,血液酯酶似乎贡献小的快速MMF体内消失。体外分析表明,人类肠微粒体暴露在5和10妈妈MMF展出水解活动2.38和4.62 nmol /(最低。分别毫克蛋白)。人类肝微粒体水解展出活动14.0和26.1 nmol /(最低。毫克的蛋白质),分别约6倍高于观察肠微粒体。MMF水解活动在人类肝细胞溶质是1.40和3.04 nmol /分钟。分别毫克蛋白)。 Because hepatic cytosols generally contain 5-fold more protein than microsomes, MMF hydrolysis in human liver cytosols corresponded to approximately 50% of that observed in microsomes. Fractions obtained by 9000g centrifugation of supernatants from COS-1 cells expressing human carboxylesterase (CES) 1 or 2 exhibited MMF hydrolytic activity, with CES1-containing fractions showing higher catalytic efficiency than CES2-containing fractions. The CES inhibitor bis-p-nitrophenylphosphate inhibited MMF hydrolysis in human liver microsomes and cytosols with IC(50) values of 0.51 and 0.36 muM, respectively. In conclusion, both intestinal and hepatic CESs and in particular CES1 may be involved in MMF hydrolysis and play important roles in MMF bioactivation. Hepatic CES1 activity levels may help explain the between-subject variability observed for MMF usage.