Guo Kunkun, Wang Xin, Huang Baolin, Wu Xiaoyun, Shen Shuimei, Lin Zimin, Zhao Jie, Cai Zheng
NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, 510515 Guangzhou, China.
NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, 510515 Guangzhou, China.
Eur J Pharm Sci. 2021 Aug 1;163:105839. doi: 10.1016/j.ejps.2021.105839. Epub 2021 Apr 20.
Gastrodin is the main active constituent of Tianma, a famous traditional Chinese herbal medicine. Our previous research has found that gastrodin is absorbed rapidly in the intestine by the sodium-dependent glucose transporter 1 (SGLT1). In the current report, gastrodin is the best glycoside compound absorbed via the glucose transport pathway. This study aimed to investigate the effect of the slight difference in chemical structure on the drug intestinal absorption via the glucose transport pathway. Traditional biopharmaceutical and computer-aided molecular docking methods were used to evaluate the intestinal absorption characteristics of three gastrodin analogues, namely, salicin, arbutin and 4-methoxyphenyl-β-D-glucoside (4-MG). The oil-water partition coefficient (logP) experiments showed that the logP values of the gastrodin analogues followed the order: 4-MG > salicin > arbutin. In vitro Caco-2 cell transport experiments demonstrated that the apparent permeability coefficient (P) value of arbutin was higher than those of salicin and 4-MG. In situ single-pass intestinal perfusion experiments showed that the absorption of arbutin and 4-MG was better than that of salicin and that the absorption of the three compounds in the colon was lower than that in the small intestine. Quantitative real-time polymerase chain reaction results confirmed that the SGLT1 mRNA expression in the small intestine of rats was obviously higher than that in the colon of rats. In vivo pharmacokinetic experiments demonstrated that the oral bioavailability of salicin was lower than those of arbutin and 4-MG. In vitro and in vivo experiments showed that glucose or phlorizin (SGLT1 inhibitor) could decrease the intestinal absorption of the three compounds. Contrary to the above biopharmaceutical experiments, the computer-aided molecular docking test showed that the affinity of salicin to the vSGLT receptor was stronger than those of arbutin and 4-MG. In conclusion, the SGLT1 can facilitate the intestinal absorption of salicin, arbutin and 4-MG, and the slight difference in chemical structure can affect absorption.
天麻素是著名的传统中草药天麻的主要活性成分。我们之前的研究发现，天麻素通过钠依赖性葡萄糖转运蛋白1（SGLT1）在肠道中快速吸收。在本报告中，天麻素是通过葡萄糖转运途径吸收的最佳糖苷化合物。本研究旨在探讨化学结构上的微小差异对药物通过葡萄糖转运途径进行肠道吸收的影响。采用传统生物药剂学和计算机辅助分子对接方法，评价了三种天麻素类似物水杨苷、熊果苷和4-甲氧基苯基-β-D-葡萄糖苷（4-MG）的肠道吸收特性。油水分配系数（logP）实验表明，天麻素类似物的logP值顺序为：4-MG＞水杨苷＞熊果苷。体外Caco-2细胞转运实验表明，熊果苷的表观渗透系数（P）值高于水杨苷和4-MG。原位单通道肠道灌注实验表明，熊果苷和4-MG的吸收优于水杨苷，且三种化合物在结肠中的吸收低于小肠。实时定量聚合酶链反应结果证实，大鼠小肠中SGLT1 mRNA表达明显高于大鼠结肠。体内药代动力学实验表明，水杨苷的口服生物利用度低于熊果苷和4-MG。体外和体内实验表明，葡萄糖或根皮苷（SGLT1抑制剂）可降低三种化合物的肠道吸收。与上述生物药剂学实验相反，计算机辅助分子对接试验表明，水杨苷与vSGLT受体的亲和力强于熊果苷和4-MG。总之，SGLT1可促进水杨苷、熊果苷和4-MG的肠道吸收，化学结构上的微小差异可影响吸收。
