Li Li, Zhu Di, Sun Xun
Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, China.
Sichuan Da Xue Xue Bao Yi Xue Ban. 2012 Nov;43(6):936-40.
To synthesize transporter-based renal targeting prodrug TPS-L-Carnitine and to determine its cellular uptake in vitro.
Triptolide (TP) was conjugated with L-carnitine using succinate as the linker to form TPS-L-Carnitine, which could be specifically recognized by OCTN2, a cationic transporter with high affinity to L-Carnitine and is highly expressed on the apical membrane of renal proximal tubule cells. Cellular uptake assays of the prodrug and its parent drug were performed on HK-2 cells, a human proximal tubule cell line, in different temperature, concentration and in the presence of competitive inhibitors.
TPS-L-Carnitine was taken up into HK-2 cells in a saturable and temperature- and concentration-dependent manner. The uptake process could be inhibited by the competitive inhibitors. The uptake of TPS-L-Carnitine was significantly higher than that of TP at 37 degrees C in the same drug concentration. TPS-L-Carnitine was taken through endocytosis mediated by transporter.
TPS-L-Carnitine provides a good renal targeting property and lays the foundation for further studies in vivo.
合成基于转运体的肾靶向前药TPS-L-肉碱，并测定其体外细胞摄取情况。
以琥珀酸为连接子，将雷公藤甲素（TP）与L-肉碱偶联形成TPS-L-肉碱，其可被OCTN2特异性识别，OCTN2是一种对L-肉碱具有高亲和力的阳离子转运体，在肾近端小管细胞的顶膜上高度表达。在不同温度、浓度以及存在竞争性抑制剂的情况下，对人近端小管细胞系HK-2细胞进行前药及其母体药物的细胞摄取实验。
TPS-L-肉碱以可饱和、温度和浓度依赖性方式被摄取到HK-2细胞中。摄取过程可被竞争性抑制剂抑制。在相同药物浓度下，37℃时TPS-L-肉碱的摄取显著高于TP。TPS-L-肉碱通过转运体介导的内吞作用被摄取。
TPS-L-肉碱具有良好的肾靶向特性，为进一步的体内研究奠定了基础。
