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目的通过比较难治性癫痫(IE)患者脑内致痫灶、灶旁组织的药物浓度的差异,促进阐明IE的耐药机制。方法收集自2007年4月~2009年3月在首都医科大学宣武医院功能神经外科行“致痫灶切除术”的IE患者。用高效液相色谱法(HPLC)测定脑组织致痫灶和灶旁组织药物浓度,比较其差异。所有患者均在术前获得知情同意。结果①共收集到23例患者的脑组织,分别服用苯巴比妥(PB)、苯妥英钠(PHT)、卡马西平(CBZ)和拉莫三嗪(LTG),将致痫灶和灶旁组织用电生理的方法进行分离,用于脑组织药物浓度的测定。剔除3例,剩余20例,包括PB 4例,CBZ 16例。②20例患者脑组织致痫灶的平均药物浓度为(1.83±0.39)μg.mL-1,灶旁组织的平均药物浓度为(2.11±0.45)μg.mL-1,采用配对t检验的方法,P=0.000<0.05,结果有统计学差异,致痫灶的药物浓度低于灶旁组织。分别观察PB组与CBZ组的结果,得出一致性结论。结论本试验的前续研究已经证实P糖蛋白(P-gp)在脑组织的致痫灶中比灶旁组织表达量多,且本试验所选药物均是P-gp的底物,在P-gp表达产物外排泵的作用下,使致痫灶中的药物浓度低于灶旁组织,导致了患者的耐药。
OBJECTIVE: To elucidate the mechanisms of drug resistance in IE by comparing the differences in drug concentrations in the epileptogenic and para-focus tissues in patients with intractable epilepsy (IE). Methods From April 2007 to March 2009 in Xuanwu Hospital, Capital Medical University, Department of Functional Neurosurgery “epileptogenic resection ” of IE patients. The concentration of drug in epileptogenic zone and para-focus tissue of brain tissue was measured by HPLC. The differences were compared. All patients received informed consent before surgery. Results Totally 23 brain tissues were collected and treated with phenobarbital (PBT), phenytoin sodium (PHT), carbamazepine (CBZ) and lamotrigine (LTG) respectively. Tissue electrophysiological methods were used for the determination of brain tissue drug concentration. Excluding 3 cases, the remaining 20 cases, including PB 4 cases, CBZ 16 cases. (2) The average drug concentration of epileptogenic zone in brain tissue of 20 patients was (1.83 ± 0.39) μg.mL-1, and the average concentration of drug in adjacent tissues was (2.11 ± 0.45) μg.mL-1. The paired t- P = 0.000 <0.05, the results were statistically significant, the drug concentration in the epileptogenic zone was lower than that in the paracancerous tissue. The results of PB group and CBZ group were observed respectively and the concordance conclusion was obtained. CONCLUSIONS: Previous studies in this trial have demonstrated that P-gp is more expressed in the focal epileptogenic zone of brain tissue than the psoas tissue and that the drugs selected for this study are substrates for P-gp. -gp expression under the action of the efflux pump, the concentration of drug in the epileptogenic zone is lower than that in the paracancer tissue, leading to the patient’s drug resistance.