ABCB1基因多态性影响日本癫痫患者对抗癫痫药物的反应。

ABCB1 polymorphisms influence the response to antiepileptic drugs in Japanese epilepsy patients.

作者信息

Seo Takayuki, Ishitsu Takateru, Ueda Nao, Nakada Naoyuki, Yurube Keigo, Ueda Kentaro, Nakagawa Kazuko

机构信息

Kumamoto University, Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Sciences, Oe-honmachi 5-1, Kumamoto 862-0973, Japan.

出版信息

Pharmacogenomics. 2006 Jun;7(4):551-61. doi: 10.2217/14622416.7.4.551.

DOI:10.2217/14622416.7.4.551

PMID:16753003

Abstract

OBJECTIVES

The efflux transporter P-glycoprotein encoded by the ATP-binding cassette (ABC)B1 gene may play a role in drug-resistant epilepsy by limiting gastrointestinal absorption and brain access of antiepileptic drugs (AEDs). Our objective was to investigate the effect of ABCB1 polymorphisms on AED responsiveness and on the pharmacokinetics of carbamazepine (CBZ) in epileptic patients with the indication for CBZ therapy.

METHODS

The ABCB1 T-129C, C1236T, G2677T/A and C3435T polymorphisms were genotyped in 210 Japanese epileptics who had been prescribed AEDs, including CBZ, for longer than 2 years. Haplotype and diplotype frequencies were estimated by expectation-maximization algorithm. Drug resistance was determined by the presence of seizures. Association of the polymorphisms with the risk of drug resistance was estimated by logistic regression analysis and the odds ratios (ORs) were adjusted for the clinical factors affecting the outcome of AED therapy. CBZ concentrations to the dose (C/D) ratios were compared among the ABCB1 polymorphisms.

RESULTS

Drug-resistant patients were more likely to have the T allele (OR [95% confidence interval (CI)], 2.02 [1.14-3.58]) and the TT genotype at C3435T (OR [95% CI], 3.64 [1.16-11.39]), and the TT genotype at G2677T/A (OR vs the GG genotype [95% CI], 3.43 [1.01-11.72]). The frequency of the T-T-T haplotype at C1236T, G2677T/A and C3435T was significantly higher (OR [95% CI], 1.84 [1.03-3.30]), and the CC-GG-CC diplotype was lower (OR [95% CI], 0.09 [0.01-0.85]) in the drug-resistant patients than in the drug-responsive patients. None of the ABCB1 polymorphisms were observed to influence the C/D ratios of CBZ.

CONCLUSION

We demonstrated that ABCB1 polymorphisms may influence the AED responsiveness without significant changes in the plasma concentrations of CBZ. Our findings were the inverse of previous results in European epileptics, thus the influence of ABCB1 polymorphisms on the AED responsiveness and/or the P-glycoprotein activity may vary among races.

摘要

目的

由ATP结合盒（ABC）B1基因编码的外排转运蛋白P-糖蛋白可能通过限制抗癫痫药物（AEDs）的胃肠道吸收和进入脑内而在耐药性癫痫中发挥作用。我们的目的是研究ABCB1基因多态性对有卡马西平（CBZ）治疗指征的癫痫患者的AED反应性及CBZ药代动力学的影响。

方法

对210名服用包括CBZ在内的AEDs超过2年的日本癫痫患者的ABCB1基因T-129C、C1236T、G2677T/A和C3435T多态性进行基因分型。通过期望最大化算法估计单倍型和双倍型频率。根据癫痫发作情况确定耐药性。通过逻辑回归分析估计多态性与耐药风险的关联，并对影响AED治疗结果的临床因素调整比值比（ORs）。比较ABCB1基因多态性之间CBZ的浓度与剂量（C/D）比值。

结果

耐药患者更可能具有T等位基因（OR[95%置信区间（CI）]，2.02[1.14 - 3.58]）以及C3435T位点的TT基因型（OR[95%CI]，3.64[1.16 - 11.39]），和G2677T/A位点的TT基因型（与GG基因型相比的OR[95%CI]，3.43[1.01 - 11.72]）。在C1236T、G2677T/A和C3435T位点的T-T-T单倍型频率在耐药患者中显著更高（OR[95%CI]，1.84[1.03 - 3.30]），而CC-GG-CC双倍型频率更低（OR[95%CI]，0.09[0.01 - 0.85]）。未观察到ABCB1基因多态性影响CBZ的C/D比值。