NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 510515 Guangzhou, China; The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, 511500 Qingyuan, China.
NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, 510515 Guangzhou, China.
Int J Pharm. 2023 Jun 10;640:123000. doi: 10.1016/j.ijpharm.2023.123000. Epub 2023 Apr 30.
Designing oral drug delivery systems using intestinal glucose transporters (IGTs) may be one of the strategies for improving oral bioavailability of drugs. However, little is known about the biological factors affecting the drug transport capacity of IGTs. Gastrodin is a sedative drug with a structure very similar to glucose. It is a highly water-soluble phenolic glucoside. It can hardly enter the intestine through simple diffusion but exhibits good oral bioavailability of over 80%. We confirmed that gastrodin is absorbed via the intestinal glucose transport pathway. It has the highest oral bioavailability among the reported glycosides' active ingredients through this pathway. Thus, gastrodin is the most selective drug substrate of IGTs and can be used to evaluate the drug transport capacity of IGTs. Obviously, strain is one of the main biological factors affecting drug absorption. This study firstly compared the drug transport capacity of IGTs between SD rats and Wistar rats and between C57 mice and KM mice by pharmacokinetic experiments and single-pass intestinal perfusion experiments of gastrodin. Then, the sodium-dependent glucose transporter type 1 (SGLT1) and sodium-independent glucose transporters type 2 (GLUT2) in the duodenum, jejunum, ileum and colon of these animals were quantified using RT-qPCR and Western blot. The results showed that the oral bioavailability of gastrodin in Wistar rats was significantly higher than in SD rats and significantly higher in KM mice than in C57 mice. Gastrodin absorption significantly differed among different intestinal segments in SD rats, C57 mice and KM mice, except Wistar rats. RT-qPCR and Western blot demonstrated that the intestinal expression distribution of SGLT1 and GLUT2 in SD rats and C57 mice was duodenum ≈ jejunum > ileum > colon. SGLT1 expression did not differ among different intestinal segments in KM mice, whereas the intestinal expression distribution of GLUT2 was duodenum ≈ jejunum ≈ ileum > colon. However, the expression of SGLT1 and GLUT2 did not differ among different intestinal segments in Wistar rats. It was reported that the intestinal expression distribution of SGLT1 and GLUT2 in humans is duodenum > jejunum > ileum > colon. Hence, the intestinal expression distribution of SGLT1 and GLUT2 of SD rats and C57 mice was more similar to that in humans. In conclusion, the drug transport capacity of IGTs differs in different strains of rats and mice. SD rats and C57 mice are more suitable for evaluating the pharmacokinetics of glycosides' active ingredients absorbed via the intestinal glucose transport pathway.
利用肠道葡萄糖转运体（IGTs）设计口服药物递送系统可能是提高药物口服生物利用度的策略之一。然而，关于影响 IGTs 药物转运能力的生物学因素知之甚少。天麻素是一种结构与葡萄糖非常相似的镇静药物。它是一种高度水溶性的酚苷。它很难通过简单扩散进入肠道，但表现出超过 80%的良好口服生物利用度。我们证实天麻素通过肠道葡萄糖转运途径被吸收。它是通过该途径吸收的报告糖苷活性成分中口服生物利用度最高的药物。因此，天麻素是 IGTs 最具选择性的药物底物，可用于评估 IGTs 的药物转运能力。显然，品系是影响药物吸收的主要生物学因素之一。本研究首先通过天麻素的药代动力学实验和单次肠灌流实验比较了 SD 大鼠和 Wistar 大鼠以及 C57 小鼠和 KM 小鼠之间 IGTs 的药物转运能力。然后，使用 RT-qPCR 和 Western blot 定量了这些动物的十二指肠、空肠、回肠和结肠中的钠依赖型葡萄糖转运体 1（SGLT1）和钠非依赖型葡萄糖转运体 2（GLUT2）。结果表明，天麻素在 Wistar 大鼠中的口服生物利用度明显高于 SD 大鼠，在 KM 小鼠中的口服生物利用度明显高于 C57 小鼠。除 Wistar 大鼠外，SD 大鼠、C57 小鼠和 KM 小鼠的不同肠段之间的天麻素吸收差异显著。RT-qPCR 和 Western blot 表明，SD 大鼠和 C57 小鼠的 SGLT1 和 GLUT2 的肠道表达分布为十二指肠≈空肠＞回肠＞结肠。在 KM 小鼠中，不同肠段之间 SGLT1 的表达没有差异，而 GLUT2 的肠道表达分布为十二指肠≈空肠≈回肠＞结肠。然而，Wistar 大鼠不同肠段之间 SGLT1 和 GLUT2 的表达没有差异。据报道，SGLT1 和 GLUT2 在人类中的肠道表达分布为十二指肠＞空肠＞回肠＞结肠。因此，SD 大鼠和 C57 小鼠的 SGLT1 和 GLUT2 肠道表达分布与人类更相似。总之，IGTs 的药物转运能力在不同品系的大鼠和小鼠中存在差异。SD 大鼠和 C57 小鼠更适合评估通过肠道葡萄糖转运途径吸收的糖苷活性成分的药代动力学。
