CYP3A4/5和ABCB1基因多态性对中国癫痫患者卡马西平单药治疗和联合治疗时卡马西平代谢及转运的影响

Effects of CYP3A4/5 and ABCB1 genetic polymorphisms on carbamazepine metabolism and transport in Chinese patients with epilepsy treated with carbamazepine in monotherapy and bitherapy.

作者信息

Wang Ping, Yin Tao, Ma Hong-Ying, Liu Dan-Qi, Sheng Yang-Hao, Wang Can, Zhou Bo-Ting

机构信息

Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.

Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Institute of Clinical Pharmacology, Central South University, Changsha, Hunan 410078, China.

出版信息

Epilepsy Res. 2015 Nov;117:52-7. doi: 10.1016/j.eplepsyres.2015.09.001. Epub 2015 Sep 9.

DOI:10.1016/j.eplepsyres.2015.09.001

PMID:26421491

Abstract

OBJECTIVE

To examine the effects of cytochrome P450 3A4 (CYP3A4), cytochrome P450 3A5 (CYP3A5) and ATP-binding cassette sub-family B member 1 (ABCB1) genetic polymorphisms on carbamazepine (CBZ) plasma concentrations in Chinese patients with epilepsy using CBZ as monotherapy and bitherapy with phenytoin (PHT), phenobarbital (PB), or valproic acid (VPA).

METHODS

Eighty-eight Chinese patients with epilepsy were recruited from Xiangya Hospital Central South University, of whom 66 patients were placed in the CBZ monotherapy group, 10 patients were placed in the CBZ bitherapy group combined with one enzyme-inducing anti-seizure medications (PHT or PB), and 12 patients were placed in the CBZ bitherapy group combined with VPA. Carbamazepine and carbamazepine-10,11-epoxide (CBZ-E) plasma concentration of these patients were measured. In addition, the genetic polymorphisms of rs4646440 and rs2242480 in the CYP3A4 gene, rs15524 and rs776746 in the CYP3A5 gene, and rs1045642, rs2032582, rs10234411 and rs1128503 in the ABCB1 gene of the cohort were genotyped. Subsequently, the associations between CBZ plasma concentrations and target single-nucleotide polymorphisms (SNPs), as well as haplotypes, were analysed.

RESULTS

In the CBZ monotherapy group, dose-adjusted CBZ concentrations were not associated with the eight SNPs and haplotypes. In the CBZ+PHT/PB group, rs776746, rs15524 and rs15524-rs776746 GT, AC haplotype were significantly associated with dose-adjusted CBZ plasma concentration (P=0.006, 0.006, 0.003, 0.003, respectively) and CBZ plus CBZ-E concentrations (P=0.006, 0.006, 0.006, 0.006, respectively); rs2032582, rs10234411 and rs2032582-rs10234411 AT, and CA haplotype were associated with the CBZ-E/CBZ ratio (P=0.007, 0.004, 0.004, 0.007, respectively).

CONCLUSIONS

rs776746 and rs15524 in the CYP3A5 gene tend to affect CBZ metabolism, and rs2032582, rs10234411 in the ABCB1 gene may contribute to inter-individual variation in CBZ and in CBZ-E transport among patients with epilepsy using CBZ in combination with PHT or PB.

摘要

目的

以卡马西平（CBZ）作为单一疗法以及与苯妥英钠（PHT）、苯巴比妥（PB）或丙戊酸（VPA）联合治疗，研究细胞色素P450 3A4（CYP3A4）、细胞色素P450 3A5（CYP3A5）和ATP结合盒转运体B家族成员1（ABCB1）基因多态性对中国癫痫患者CBZ血药浓度的影响。

方法

从中南大学湘雅医院招募88例中国癫痫患者，其中66例患者纳入CBZ单一疗法组，10例患者纳入CBZ与一种酶诱导抗癫痫药物（PHT或PB）联合治疗组，12例患者纳入CBZ与VPA联合治疗组。测定这些患者的CBZ及卡马西平 - 10,11 - 环氧化物（CBZ - E）血药浓度。此外，对该队列中CYP3A4基因的rs4646440和rs2242480、CYP3A5基因的rs15524和rs776746以及ABCB1基因的rs1045642、rs2032582、rs10234411和rs1128503进行基因分型。随后，分析CBZ血药浓度与目标单核苷酸多态性（SNP）以及单倍型之间的关联。

结果

在CBZ单一疗法组中，剂量调整后的CBZ浓度与8个SNP及单倍型均无关联。在CBZ + PHT/PB组中，rs776746、rs15524以及rs15524 - rs776746 GT、AC单倍型与剂量调整后的CBZ血药浓度显著相关（P分别为0.006、0.006、0.003、0.003）以及CBZ加CBZ - E浓度（P分别为0.006、0.006、0.006、0.006）；rs2032582、rs10234411以及rs2032582 - rs10234411 AT和CA单倍型与CBZ - E/CBZ比值相关（P分别为0.007、0.004、0.004、0.007）。