Jin Cheng-Hao, Chae Su Young, Son Sohee, Kim Tae Hyung, Um Key An, Youn Yu Seok, Lee Seulki, Lee Kang Choon
College of Pharmacy, SungKyunKwan University, Jangan-ku, Suwon City, South Korea.
J Control Release. 2009 Feb 10;133(3):172-7. doi: 10.1016/j.jconrel.2008.09.091. Epub 2008 Oct 21.
An orally active glucagon-like peptide-1 (GLP-1) formulation would have great advantages over conventional injectable therapies for the treatment of diabetic patients. Because GLP-1 absorption in the intestine is restricted by its natural physiological characteristics, biotinylated exendin-4 analogues might useful as orally active GLP-1 receptor agonists. Three different biotinylated exendin-4 analogues, Lys(27)-Biotin-Exendin-4 (MB1-Ex-4), Lys(12)-Biotin-Exendin-4 (MB2-Ex-4), and Lys(12, 27)-Biotin-Exendin-4 (DB-Ex-4) were prepared, and their biological activities and enzymatic stabilities were studied in vitro. The hypoglycemic effects and pharmacokinetics of these analogues after oral administration were evaluated in db/db mice and Sprague-Dawley rats, respectively. These biotinylated exendin-4 analogues preserved GLP-1 receptor binding affinity and stimulated insulin secretion in RIN-m5F murine insulinoma cells and in isolated rat islets, respectively, and were as potent as exendin-4. In particular, DB-Ex-4 showed 9.0-fold better stability against rat intestinal fluid than exendin-4. When 0.1, 1, and 10 microg/mouse of DB-Ex-4 were orally administered, mean total hypoglycemic degrees (HGD) were increased by 36.8+/-1.2, 46.9+/-1.8, and 54.3+/-4.5%, respectively, whereas 1 microg/mouse of native exendin-4 showed an increase of 8.8+/-7.3%. This study demonstrates that biotinylated exendin-4 analogues are absorbed in the intestine and that they have biological efficacies of exendin-4. Furthermore, it indicates that biotinylated exendin-4 analogues could be used as potential oral antidiabetic agent for the treatment of type 2 diabetes.
一种口服活性胰高血糖素样肽-1（GLP-1）制剂在治疗糖尿病患者方面比传统注射疗法具有很大优势。由于GLP-1在肠道中的吸收受其天然生理特性限制，生物素化艾塞那肽-4类似物可能作为口服活性GLP-1受体激动剂有用。制备了三种不同的生物素化艾塞那肽-4类似物，即赖氨酸（27）-生物素-艾塞那肽-4（MB1-Ex-4）、赖氨酸（12）-生物素-艾塞那肽-4（MB2-Ex-4）和赖氨酸（12,27）-生物素-艾塞那肽-4（DB-Ex-4），并在体外研究了它们的生物学活性和酶稳定性。分别在db/db小鼠和Sprague-Dawley大鼠中评估了这些类似物口服给药后的降血糖作用和药代动力学。这些生物素化艾塞那肽-4类似物分别在RIN-m5F小鼠胰岛素瘤细胞和分离的大鼠胰岛中保留了GLP-1受体结合亲和力并刺激胰岛素分泌，且与艾塞那肽-4一样有效。特别是，DB-Ex-4对大鼠肠液的稳定性比艾塞那肽-4高9.0倍。当以0.1、1和10μg/小鼠口服给予DB-Ex-4时，平均总降血糖程度（HGD）分别增加36.8±1.2%、46.9±1.8%和54.3±4.5%，而1μg/小鼠的天然艾塞那肽-4增加了8.8±7.3%。本研究表明生物素化艾塞那肽-4类似物在肠道中被吸收且具有艾塞那肽-4的生物学功效。此外，这表明生物素化艾塞那肽-4类似物可作为治疗2型糖尿病的潜在口服抗糖尿病药物。
