Role of Taurine Transporter in the Retinal Uptake of Vigabatrin
Role of Taurine Transporter in the Retinal Uptake of Vigabatrin
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DOI：
10.1208/s12249-020-01736-7
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发表时间：
2020-07-14
影响因子：
3.3
通讯作者：
Murthy, S. Narasimha
中科院分区：
文献类型：
--
作者：
Police, Anitha;Shankar, Vijay Kumar;Murthy, S. Narasimha
维卡他林(VGB)是治疗婴儿痉挛的一线药物。在治疗剂量上，VGB在视网膜内积聚，导致永久性的周边视野收缩。VGB在视网膜积聚的机制尚不明确。本研究对VGB进入视网膜的机制进行了探讨。以成人视网膜色素上皮(ARPE-19)细胞作为体外血视网膜屏障模型，研究了VGB在体外视网膜的摄取。VGB细胞摄取研究表明，VGB细胞摄取呈饱和动力学，K-m值为13.1 mm，在pH 7.4和高渗条件下摄取显着增加，表明载体介导的Na+-Cl-依赖转运体参与了摄取。在牛磺酸转运蛋白底物(牛磺酸和GABA)和阻断剂金刚乙基磺酸盐(GES)的存在下，VGB的摄取显著减少，说明TauT对VGB的摄取有贡献。长期给予GES和牛磺酸后，大鼠视网膜VGB水平分别下降1.5倍和1.3倍。综上所述，这项研究证实了TRAT参与了VGB在视网膜的摄取和积累。
Vigabatrin (VGB) is a first-line drug used for treatment of infantile spasms. On therapeutic dose, VGB accumulates in the retina causing permanent peripheral visual field constriction. The mechanism involved in retinal accumulation of VGB is ambiguous. In the present study, mechanism of VGB transport into retina was evaluated. VGB uptake into retina was studied in vitro using human adult retinal pigment epithelial (ARPE-19) cells as a model for outer blood retinal barrier. The VGB cell uptake studies demonstrated saturation kinetics with K-m value of 13.1 mM and uptake was significantly increased at pH 7.4 and hyperosmolar conditions indicating involvement of carrier-mediated Na+-Cl--dependent transporter. In the presence of taurine transporter (TauT) substrates (taurine and GABA) and inhibitor guanidinoethyl sulfonate (GES), the uptake of VGB decreased significantly demonstrating contribution of TauT. The VGB retinal levels in rats were decreased by 1.5- and 1.3-folds on chronic administration of GES and taurine, respectively. In conclusion, this study demonstrated the TauT involvement in VGB uptake and accumulation in retina.