P-糖蛋白对卡马西平和苯妥英钠通过大鼠血脑屏障影响的研究

P-glycoprotein involved in regulation of penetration of carbamazepine and phenytoin through blood-brain barrier

目的观察P糖蛋白(Pglycoprotein,PGP)拮抗剂维拉帕米对卡马西平和苯妥英钠通过大鼠血脑屏障的影响,探讨PGP在难治性癫癎多药耐药机制中的作用。方法在健康大鼠大脑皮质内安置微透析探针,腹腔注射卡马西平(20mg/kg)和苯妥英钠(50mg/kg),在给药后不同时间点收集透析液,并用高效液相技术检测其中的药物浓度,通过微透析探针局部给予维拉帕米,观察后者能否提高大鼠皮质脑细胞外液中抗癫药物的浓度。结果维拉帕米升高了脑细胞外液中卡马西平[60min:(1.74±0.28)μg/ml,90min:(1.87±0.31)μg/ml]和苯妥英钠[30min:(1.08±0.30)μg/ml;60min:(1.54±0.22)μg/ml;150min:(0.91±0.19)μg/ml]的药物浓度,前者在给药后60～90min显著增高(P<0.05),后者在给药后30～150min显著增高(P<0.05)。结论PGP限制卡马西平和苯妥英钠顺利通过血脑屏障,降低脑皮质细胞外液抗癫癎药物浓度,难治性癫时PGP表达增加可能是引起患者对抗癫癎药物产生多药耐药的原因。

Objective To study the effect of P-glycoprotein （PGP） in regulation of penetration of carbamazepine and phenytoin through blood-brain barrier, as to indicating the entry of epileptic drugs into the brain restricted by PGP and deducing the muhidrug resistance mechanisms of refractory epilepsy.Methods The microdialysis probe was placed into the cortex of rats, and after systemic injection of carbamazepine and phenytoin, dialysate was collected and the antiepiletic drug concentration in the extracellular fluid of the cerebral cortex was determined by high-performance liquid chromatography （HPLC）. Then observing whether the concentration of drugs in extracellular fluid can be enhanced by PGP＇s inhibitor verapamil. Results Verapamil significantly enhanced the concentration of carbamazepine in extracellulax fluid of the cerebral cortex during 60-90 minutes after injection （ （ 1.74 ± 0. 28 ）μ/ml in 60 minutes and （ 1.87±0. 31 ） μg/ml in 90 minutes ,P 〈0. 05 ） , phenytoin was also enhanced during 30-150 minutes after injection （ 30 minutes： （ 1.08± 0. 30 ） μg/ml, 60 minutes： （ 1.54±0. 22 ） μg/ml and 150 minutes：（0.91±0. 19） μg/ml, P 〈0.05）. Conclusions Penetration of carbamazepine and phenytoin through blood-brain barrier should be restricted by PGP, and PGP might decrease the antiepiletic drug concentration in the extracellular fluid of the cerebral cortex, So the increased expression of PGP in brains of epileptic patients might be an important mechanism of multidrug resistance of refractory epilepsy.