多药转运蛋白对匹罗卡品癫痫大鼠模型脑内拉莫三嗪浓度的影响  

Impact of multi-drug transporters on regulation of concentration of lamotrigine in hippocampal extracellular fluid in rat after pilocarpine-induced seizures

作　　者：马爱梅[1] 张守文[2] 刘玉玺[2] 胡风云[1] 

机构地区：[1]山西省人民医院神经内科,太原030012 [2]山西医科大学第三医院神经内科

出　　处：《中华神经科杂志》2009年第8期551-554,共4页Chinese Journal of Neurology

基　　金：基金项目：山西省青年科技研究基金资助项目（2006021044）

摘　　要：目的观察多药转运蛋白[P-糖蛋白（P—glycoprotein，PGP）和多药耐药相关蛋白（multi—drugresistanceassociatedprotein，MRP）]对匹罗卡品慢性癫痫大鼠模型海马内拉莫三嗪浓度的影响，探讨PGP和MRP在难治性癫痫多药耐药机制中的作用。方法建立匹罗卡品慢性癫痫动物模型，在模型大鼠海马内安置微透析探针，腹腔注射拉莫三嗪（10ms／kg）后于不同时间点收集透析液，并用高效液相色谱检测其中的药物浓度。通过微透析探针局部分别给予PGP拮抗剂维拉帕米和MRP拮抗剂丙磺舒，观察维拉帕米和丙磺舒对模型鼠海马内神经元细胞外液拉莫三嗪浓度的影响。结果维拉帕米明显升高了癫痫大鼠海马细胞外液拉莫三嗪的药物浓度，在给药后60、90、120、150min（0．65±0．11、0．84±0．09、0．70±0．09和0．58±0．08）与模型组（0．41±0．10、0．50±0．04、0．39±0．09和0．30±0．06）比较差异有统计学意义（F=5．01、8．61、10．23、7．89，P〈0．05），丙磺舒也提高了海马内拉莫三嗪的浓度，给药后90、120、150min（0．75±0．09、0．58±0．10和0．49±0．07）与模型组比较差异有统计学意义（F=6．58、4．56、4．75，P〈0．05）。结论PGP和MRP均能够限制拉莫三嗪通过癫痫大鼠血脑屏障，从而降低了海马内拉莫三嗪的药物浓度，上述机制可能参与了难治性癫痫耐药的发生。Objective To investigate the impact of multi-drug transporters including P-glycoprotein （PGP） and multi-drug resistance associated protein （MRP） on concentration of lamotrigine in the extracellular fluid in hippocampus of epilepsy rat models induced by pilocarpine, and to deduce the multidrug resistance mechanisms in refractory epilepsy. Methods The epilepsy rat models were established by repeated administration （by ip） of pilocarpine. A microdialysis probe was placed into the hippocampus of the epileptic rats and dialysate was collected at five time-points from 30--150 minutes after systemic injections of lamotrigine （ 10 mg/kg）. The concentration of lamotrigine in the extracellular fluid in the hippocampus was determined by high-performance liquid chromatography （HPLC）. Then PGP inhibitor verapamil and MRP inhibitor probenecid was added individually through microdialysis probe and the concentration of lamotrigine was detected again. Results Compared with control group （0. 41 ± 0. 10 in 60 minutes, 0. 50± 0.04 in 90 minutes, 0. 39 ± 0. 09 in 120 minutes and 0. 30 ± 0. 06 in 150 minutes）, verapamil significantly increased the concentration of lamotrigine in extracellular fluid of the hippocampus 60--150 minutes （0. 65 ±0. 11, 0. 84 ±0. 09, 0. 70 ±0. 09 and 0. 58 ±0. 08 respectively） after injection （ F value were 5.01, 8.61, 10. 23 and 7.89, all P 〈 0. 05） and probenecid also enhanced the concentration of lamotrigine 90--150 minutes （0. 75 ± 0. 09, 0. 58 ± 0. 10 and 0.49 ± 0.07 ） after injection （ F = 6. 58, 4. 56, 4. 75, all P 〈 0. 05 ）. Conclusions Penetration of lamotrigine through blood-brain barrier in pilocarpine induced epilepsy rats is restricted by PGP and MRP, resulting in decreased concentration of lamotrigine in the extracellular fluid of the hippocampus. Therefore, increasing expression of PGP and MRP in brains of epilepsy patients might be an important mechanism involved in multi-drug resistance in refractory epilepsy.

关 键 词：癫痫 P糖蛋白类 多药耐药相关蛋白 三嗪类 疾病模型 动物 

分 类 号：R686[医药卫生—骨科学]