Department of Pharmacy, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, China.
DNA Cell Biol. 2019 Mar;38(3):250-255. doi: 10.1089/dna.2018.4553. Epub 2019 Jan 11.
P-glycoprotein (P-gp), encoded by the MDR1 (multidrug resistance 1) gene, involves in the efflux of multiple compounds, such as certain antiepileptic drugs. The aim of this research was to observe the impacts of MDR1 (C3435T) variant on the efflux of phenytoin, carbamazepine, valproate, and phenobarbital in vitro. Stable recombinant LLC-PK1 cell systems transfected with MDR1 (wild-type allele) and MDR1 (variant allele) were constructed. The influences of MDR1 (C3435T) variant on the sensitivity, intracellular accumulation, and transepithelial permeability of antiepileptic drugs were assessed. The recombinant MDR1 cells showed higher resistance to carbamazepine compared with MDR1 cells in the cytotoxicity assay (p < 0.01). The intracellular accumulation of carbamazepine was significantly decreased in cells transfecting with MDR1 allele when compared with recombinant MDR1 cells (p < 0.01). These results also indicate that the efflux activity of P-gp-mediated carbamazepine in recombinant MDR1 cells was greatly increased compared with MDR1 cells (p < 0.01), whereas the transport ability of P-gp-dependent phenobarbital in recombinant MDR1 cells was significantly lower than MDR1 cells (p < 0.01). However, the effects of MDR1 (C3435T) polymorphism on the resistance, intracellular accumulation, and efflux of phenytoin and valproate were not found in this study. MDR1 variant allele might be more efficient to transport carbamazepine, whereas reduces the efflux activity of P-gp-mediated phenobarbital. Collectively, MDR1 (C3435T) polymorphism might impact the P-gp activity and antiepileptic agents efflux with drug specificity.
P-糖蛋白（P-gp）由多药耐药基因 1（MDR1）编码，参与多种化合物的外排，如某些抗癫痫药物。本研究旨在观察 MDR1（C3435T）变异对体外苯妥英、卡马西平、丙戊酸和苯巴比妥外排的影响。构建了稳定转染 MDR1（野生型等位基因）和 MDR1（变异型等位基因）的 LLC-PK1 细胞重组系统。评估了 MDR1（C3435T）变异对抗癫痫药物敏感性、细胞内积累和跨上皮通透性的影响。细胞毒性测定显示，与 MDR1 细胞相比，重组 MDR1 细胞对卡马西平的耐药性更高（p<0.01）。与重组 MDR1 细胞相比，转染 MDR1 等位基因的细胞内卡马西平积累显著减少（p<0.01）。这些结果还表明，与 MDR1 细胞相比，重组 MDR1 细胞中 P-gp 介导的卡马西平外排活性大大增加（p<0.01），而 P-gp 依赖性苯巴比妥在重组 MDR1 细胞中的转运能力明显低于 MDR1 细胞（p<0.01）。然而，本研究未发现 MDR1（C3435T）多态性对苯妥英和丙戊酸的耐药性、细胞内积累和外排的影响。MDR1 变异等位基因可能更有效地转运卡马西平，而降低 P-gp 介导的苯巴比妥外排活性。总之，MDR1（C3435T）多态性可能会影响 P-gp 活性和药物特异性的抗癫痫药物外排。
