Yang Hui-Wen, Liu Hai-Yan, Liu Xiang, Zhang Dong-Mei, Liu Yu-Chun, Liu Xiao-Dong, Wang Guang-Ji, Xie Lin
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Neurosci Lett. 2008 Apr 4;434(3):299-303. doi: 10.1016/j.neulet.2008.01.071. Epub 2008 Feb 6.
To investigate whether long-term exposure to four typical antiepileptic drugs (AEDs): phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ) and valproic acid (VPA) can increase P-glycoprotein (P-gp) level and function in primary cultured rat brain microvascular endothelial cells (rBMECs) in vitro, the rBMECs were incubated in culture medium containing indicated drugs (PB, PHT, CBZ, VPA and rifampin) for 60 days in a gradient concentration manner. Age-matched cells were incubated in normal culture medium. After a 60-day exposure to the indicated drugs, P-gp function and level in cells were measured using rhodamine 123 (Rho123) accumulations and Western blot analysis, respectively. Lower Rho123 accumulation in drug-treated cells was found than that in age-matched cells. Cyclosporin A (CsA) and verapamil (Ver) increased Rho123 accumulation both in drug-treated cells and age-matched cells. The magnitude of increased Rho123 accumulation in drug-treated cells was larger than that in age-matched cells. Higher P-gp levels were found to be consistent with decrease of Rho123 accumulation in drug-treated cells. The results verified the hypothesis that long-term exposure to the four antiepileptic drugs can induce P-gp function and level in rBMECs.
为了研究长期暴露于四种典型抗癫痫药物（AEDs）：苯巴比妥（PB）、苯妥英（PHT）、卡马西平（CBZ）和丙戊酸（VPA）是否会增加原代培养的大鼠脑微血管内皮细胞（rBMECs）中P-糖蛋白（P-gp）的水平和功能，将rBMECs以梯度浓度方式在含有指定药物（PB、PHT、CBZ、VPA和利福平）的培养基中孵育60天。年龄匹配的细胞在正常培养基中孵育。在对指定药物进行60天的暴露后，分别使用罗丹明123（Rho123）蓄积和蛋白质印迹分析来测量细胞中P-gp的功能和水平。发现药物处理细胞中的Rho123蓄积低于年龄匹配细胞中的蓄积。环孢素A（CsA）和维拉帕米（Ver）在药物处理细胞和年龄匹配细胞中均增加了Rho123蓄积。药物处理细胞中Rho123蓄积增加的幅度大于年龄匹配细胞中的幅度。发现较高的P-gp水平与药物处理细胞中Rho123蓄积的减少一致。结果证实了长期暴露于这四种抗癫痫药物可诱导rBMECs中P-gp功能和水平的假说。
