去羟肌苷拟肉毒碱类前药的合成及膜渗透性评价  

The synthesis and membrane permeability assessment of didanosine prodrug targeting carnitine transporter 2

作　　者：张又夕 孙乐[2] 马海英[1] ZHANG Youxi;SUN Le;MA Haiying(Department of Pharmacy,the Fourth Affiliated Hospital of China Medical University,Shenyang 110032,China;School of Pharmacy,China Medical University,Shenyang 110122,China)

机构地区：[1]中国医科大学附属第四医院药学部,辽宁沈阳110032 [2]中国医科大学药学院,辽宁沈阳110122

出　　处：《沈阳药科大学学报》2020年第5期390-394,共5页Journal of Shenyang Pharmaceutical University

基　　金：辽宁省科技厅博士启动基金项目(201601120);国家自然科学基金青年基金资助项目(81603055)。

摘　　要：目的设计基于肠道肉毒碱转运蛋白的前体药物以提高药物的口服吸收。方法以去羟肌苷为母体药物,L-肉毒碱-丁二酸或L-肉毒碱-庚二酸为功能修饰侧链,设计合成了新型去羟肌苷拟肉毒碱类前药,其结构经ESI/MS及13C-NMR数据确证,用Caco-2细胞转运实验评价了该类前药的细胞膜渗透性,用HEK293T和Caco-2细胞考察了该类前药的摄取机制。结果合成了两个前药,其Caco-2细胞膜渗透性均比母体药物去羟肌苷有显著的提高,且该类前药在Caco-2细胞中的摄取率比在HEK293T中的摄取率显著升高。结论肉毒碱功能化修饰去羟肌苷的5’位羟基有利于提高其口服吸收。Objective To design the didanosine prodrug targeting intestinal carnitine transporter 2 for improved oral absorption.Methods A novel prodrug of didanosine targeting carnitine transporter 2 was synthesized using didanosine as a parent drug and L-carnitine-succinic acid as functionally modified side chain.The structures of those prodrugs were confirmed by ESI/MS and 13C-NMR.Moreover,the cell membrane permeability of the prodrugs was assessed by Caco-2 cell transport experiment,the HEK293 T and Caco-2 cell uptake of the prodrugs were also determined.Results Two L-carnitine prodrugs of didanosine were synthesized,whose Caco-2 cells membrane permeability abilities were significantly improved compared to the parent drug.Moreover,the Caco-2 cellular uptake of the prodrugs was much higher than the HEK293 T cell uptake.Conclusion The functional modification of L-carnitine to 5’-OH of didanosine is helpful for improving oral bioavailability of didanosine.

关 键 词：去羟肌苷 肉毒碱转运蛋白 前药 口服吸收 

分 类 号：R94[医药卫生—药剂学]