A novel oral prodrug-targeting transporter MCT 1: 5-fluorouracil-dicarboxylate monoester conjugates  

作　　者：Yixin Sun Dongyang Zhao Gang Wang Qikun Jiang Mengran Guo Qiming Kan Zhonggui He Jin Sun 

机构地区：[1]Wuya College of Innovation,Shenyang Pharmaceutical University,Shenyang 110016,China [2]School of Pharmacy,Guangxi University of Chinese Medicine,Nangning 530200,China [3]School of Pharmacy,Shenyang Pharmaceutical University,No.103,Wenhua Road,Shenyang 110016,China [4]School of Life Science and Biopharmaceutics,Shenyang Pharmaceutical University,Shenyang 110016,China

出　　处：《Asian Journal of Pharmaceutical Sciences》2019年第6期631-639,共9页亚洲药物制剂科学（英文）

基　　金：financially Supported by National Nature Sci-ence Foundation of China(No.81773656,U1608283,81573497);Liaoning Revitalization Talents Program,No XLYC1808017,Key projects of Technology bureau in Shenyang,No18400408;Key projects of Liaoning Province Department of Education,No.2017LZD03

摘　　要：Monocarboxylate transporter 1(MCT1)is responsible for oral absorption of short-chain monocarboxylic acids from small intestine,hence,it’s likely to serve as an ideal design target for the development of oral prodrugs.However,potential application of MCT1 to facilitate the oral delivery is still unclear.Irregular oral absorption,poor permeability and bioavailability greatly limit the oral delivery efficiency of 5-fluorouracil(5-FU).Herein,we design three 5-FU-fatty acid conjugates targeting intestinal MCT1 with different lipophilic linkages.Interestingly,due to high MCT1 affinity and good gastrointestinal stability,5-FUoctanedioic acid monoester prodrug exhibited significant improvement in membrane permeability(13.1-fold)and oral bioavailability(4.1-fold)compared to 5-FU.More surprisingly,stability experiment in intestinal homogenates showed that 5-FU prodrugs could be properly activated to release 5-FU within intestinal cells,which provides an ideal foundation for the improvement of oral bioavailability.In summary,good gastrointestinal stability,high membrane permeability and appropriate intestinal cell bioactivation are the important factors for high-efficiency 5-FU oral prodrugs,and such work provides a good platform for the development of novel oral prodrugs targeting intestinal transporters.Monocarboxylate transporter 1(MCT1) is responsible for oral absorption of short-chain monocarboxylic acids from small intestine, hence, it’s likely to serve as an ideal design target for the development of oral prodrugs. However, potential application of MCT1 to facilitate the oral delivery is still unclear. Irregular oral absorption, poor permeability and bioavailability greatly limit the oral delivery efficiency of 5-fluorouracil(5-FU). Herein, we design three 5-FU-fatty acid conjugates targeting intestinal MCT1 with different lipophilic linkages. Interestingly, due to high MCT1 affinity and good gastrointestinal stability, 5-FUoctanedioic acid monoester prodrug exhibited significant improvement in membrane permeability(13.1-fold) and oral bioavailability(4.1-fold) compared to 5-FU. More surprisingly, stability experiment in intestinal homogenates showed that 5-FU prodrugs could be properly activated to release 5-FU within intestinal cells, which provides an ideal foundation for the improvement of oral bioavailability. In summary, good gastrointestinal stability, high membrane permeability and appropriate intestinal cell bioactivation are the important factors for high-efficiency 5-FU oral prodrugs, and such work provides a good platform for the development of novel oral prodrugs targeting intestinal transporters.

关 键 词：5-FLUOROURACIL PRODRUGS Monocarboxylate TRANSPORTER 1 Permeability ORAL bioavailability 

分 类 号：R73[医药卫生—肿瘤]