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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 investigate the effect of verapamil, a PGP antagonist, on the blood-brain barrier of rats through carbamazepine and phenytoin sodium, and to explore the role of PGP in multidrug resistance in refractory epilepsy. Methods Microdialysis probes were placed in the cerebral cortex of healthy rats. Carbamazepine (20 mg / kg) and phenytoin sodium (50 mg / kg) were injected intraperitoneally. Dialysate was collected at different time points after administration and detected by HPLC The drug concentration was given locally to the verapamil by a microdialysis probe to see if the latter increases the concentration of anti-epileptic drugs in extracellular fluid of rat cortical brain. Verapamil increased carbamazepine (60 min: 1.74 ± 0.28 μg / ml, 90 min: (1.87 ± 0.31) μg / ml] and phenytoin [30 min: (1.08 ± 0.30) (1.54 ± 0.22) μg / ml; 150min: (0.91 ± 0.19) μg / ml], the former was significantly increased 60-90min after administration (P <0.05) After 30 ~ 150min significantly increased (P <0.05). Conclusions PGP limits the smooth passage of carbamazepine and phenytoin through the blood-brain barrier and decreases the concentration of anti-epileptic drugs in cerebral cortical extracellular fluid. Increased PGP expression in refractory epilepsy may be caused by multidrug resistance in patients with epilepsy. the reason.