Bournissen Facundo Garcia, Moretti Myla E, Juurlink David N, Koren Gideon, Walker Mugabe, Finkelstein Yaron
Divisions of Clinical Pharmacology and Toxicology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Epilepsia. 2009 Apr;50(4):898-903. doi: 10.1111/j.1528-1167.2008.01858.x. Epub 2008 Oct 24.
Approximately one-third of patients with epilepsy patients have recurrent seizures despite therapy. It has been suggested that therapeutic failure is associated with high expression of the multidrug efflux ABCB1 (MDR1) drug-transporter; specifically, that patients with the 3435CC genotype have higher efflux of anticonvulsants out of brain tissue, with correspondingly lower concentrations in the central nervous system.
We conducted a meta-analysis to examine the association between MDR1 polymorphisms and the response to anticonvulsants. We included all published studies until September 2007, in which patients with responsive and unresponsive seizure disorders underwent genotyping for ABCB1 C3435T. Individual and summary odds ratios were calculated using a random effects model. A secondary analysis was also performed, stratifying the studies by their ethnic distribution to account for genetic heterogeneity. We also performed a cumulative analysis by date of publication for the included studies using a random effects model.
We identified 11 case-control studies involving 3,371 patients (1,646 patients with drug-resistant epilepsy and 1,725 controls). We identified no significant association between anticonvulsant drug resistance and MDR1 polymorphism [odds ratio 1.15; 95% confidence interval (CI) 0.78-1.70; p = 0.48). Subanalysis of studies according to ethnicity yielded similar findings [European cohort: OR = 1.31; 95% CI 0.89-1.94, p = 0.18; Asian cohort: OR = 0.99; 95% CI 0.51-1.89, p = 0.96).
We found no association between ABCB1 genotype and response to anticonvulsant drugs. At the present time, genetic typing for MDR1 polymorphism is not warranted for patients with drug-resistant epilepsy.
尽管接受了治疗，但约三分之一的癫痫患者仍会反复发作。有人提出，治疗失败与多药外排ABCB1（MDR1）药物转运蛋白的高表达有关；具体而言，具有3435CC基因型的患者脑组 织中抗惊厥药的外排较高，相应地中枢神经系统中的浓度较低。
我们进行了一项荟萃分析，以研究MDR1基因多态性与抗惊厥药反应之间的关联。我们纳入了截至2007年9月所有已发表的研究，其中对有反应和无反应的癫痫患者进行了ABCB1 C3435T基因分型。使用随机效应模型计算个体和汇总比值比。还进行了一项次要分析，根据种族分布对研究进行分层，以考虑基因异质性。我们还使用随机效应模型对纳入研究按发表日期进行了累积分析。
我们确定了11项病例对照研究，涉及3371名患者（1646名耐药性癫痫患者和1725名对照）。我们发现抗惊厥药物耐药性与MDR1基因多态性之间无显著关联[比值比1.15；95%置信区间（CI）0.78 - 1.70；p = 0.48]。根据种族对研究进行的亚分析得出了类似的结果[欧洲队列：OR = 1.31；95%CI 0.89 - 1.94，p = 0.18；亚洲队列：OR = 0.99；95%CI 0.51 - 1.89，p = 0.96]。
我们发现ABCB1基因型与抗惊厥药物反应之间无关联。目前，对于耐药性癫痫患者，不建议进行MDR1基因多态性的基因分型。
