Department of Pharmacy, People's Hospital of Xinjiang Uygur Autonomous Region.
Institute of Clinical Pharmacy, People's Hospital of Xinjiang Uygur Autonomous Region.
Ther Drug Monit. 2022 Jun 1;44(3):455-464. doi: 10.1097/FTD.0000000000000927. Epub 2021 Oct 5.
P-glycoprotein, encoded by ABCB1 (or MDR1), may contribute to drug resistance in epilepsy by limiting gastrointestinal absorption and brain access to antiseizure medications. The study aimed to evaluate the impact of ABCB1 polymorphisms on lacosamide (LCM) serum concentrations in Uygur pediatric patients with epilepsy.
The serum concentrations of LCM were determined by ultrahigh performance liquid chromatography, and the ABCB1 polymorphism was analyzed through polymerase chain reaction-fluorescence staining in situ hybridization. The χ2 test and the Fisher exact test were used to analyze the allelic and genotypic distributions of ABCB1 polymorphisms between the drug-resistant and drug-responsive patient groups. Differences in steady-state and dose-corrected LCM serum concentrations between different genotypes were analyzed using the one-way analysis of variance and the Mann-Whitney test.
A total of 131 Uygur children with epilepsy were analyzed, and of them, 41 demonstrated drug resistance. The frequency of the GT genotype of ABCB1 G2677T/A was significantly higher in the drug-resistant group than that in the drug-responsive group (P < 0.05, OR = 1.966, 95% CI, 1.060-3.647). Patients with the G2677T/A-AT genotype had a statistically significantly lower concentration-to-dose (CD) value than patients with the G2677T/A-GG genotype (mean: 0.6 ± 0.2 versus 0.8 ± 0.5 mcg/mL per mg/kg, P < 0.001). Significantly lower LCM serum concentrations were observed in ABCB1 C3435T CT and TT genotype carriers than those in the CC carriers (P = 0.008 and P = 0.002), and a significantly lower LCM CD value was observed in ABCB1 C3435T CT genotype carriers than that in the CC carriers (P = 0.042).
ABCB1 G2677T/A and C3435T polymorphisms may affect LCM serum concentrations and treatment efficacy in Uygur pediatric patients with epilepsy, leading to drug resistance in pediatric patients.
P-糖蛋白（ABCB1 或 MDR1 编码）可能通过限制胃肠道吸收和抗癫痫药物进入大脑，导致癫痫患者产生药物耐药性。本研究旨在评估 ABCB1 多态性对维吾尔族癫痫患儿拉科酰胺（LCM）血清浓度的影响。
采用超高效液相色谱法测定 LCM 血清浓度，通过聚合酶链反应-荧光原位杂交分析 ABCB1 多态性。采用 χ2 检验和 Fisher 确切概率法分析耐药组和敏感组患者 ABCB1 多态性的等位基因和基因型分布。采用单因素方差分析和 Mann-Whitney 检验分析不同基因型间稳态和剂量校正后 LCM 血清浓度的差异。
共分析 131 例维吾尔族癫痫患儿，其中 41 例为耐药。耐药组 ABCB1 G2677T/A 的 GT 基因型频率明显高于敏感组（P<0.05，OR=1.966，95%CI，1.060-3.647）。G2677T/A-AT 基因型患者的浓度-剂量（CD）值明显低于 G2677T/A-GG 基因型患者（均值：0.6±0.2 比 0.8±0.5 mcg/mL 每 mg/kg，P<0.001）。ABCB1 C3435T CT 和 TT 基因型携带者的 LCM 血清浓度明显低于 CC 携带者（P=0.008 和 P=0.002），ABCB1 C3435T CT 基因型携带者的 LCM CD 值明显低于 CC 携带者（P=0.042）。
ABCB1 G2677T/A 和 C3435T 多态性可能影响维吾尔族癫痫患儿的 LCM 血清浓度和治疗效果，导致儿科患者产生耐药性。
