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首页> 外文期刊>Journal of pharmaceutical sciences. >Pharmacokinetic and pharmacodynamic evaluation of site-specific PEGylated glucagon-like peptide-1 analogs as flexible postprandial-glucose controllers.
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Pharmacokinetic and pharmacodynamic evaluation of site-specific PEGylated glucagon-like peptide-1 analogs as flexible postprandial-glucose controllers.

机译：作为灵活的餐后葡萄糖控制剂的位点特异性PEG化胰高血糖素样肽1类似物的药代动力学和药效学评估。

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The rapid elimination of glucagon-like peptide-1 (GLP-1) is the main impediment to its anti-diabetic utility. Here, we tried to improve its poor pharmacokinetic/pharmacodynamic profiles using PEGylation. The site-specific (Lys(34)) PEGylated GLP-1s were synthesized with PEGs of 2, 5, and 10 kDa, respectively. Oral glucose tolerance tests using db/db mice showed that these three PEGylated GLP-1s (5 nmol/kg) specifically stabilized plasma glucose levels when intraperitoneally (i.p.) administered at 30, 30-120, or 120-360 min preoral glucose treatment, respectively (total hypoglycemic degree: 60.5 +/- 5.0%, approximately 67.2 +/- 2.3%, and approximately 59.4 +/- 4.3%, respectively). Particularly, Lys(34)-PEG(10K)-GLP-1 showed an stable hypoglycemic efficacy when administered up to 360 min preglucose. The different anti-diabetic effects of PEGylated GLP-1s were attributed to their augmented pharmacokinetics and metabolic resistance. These analogs had higher metabolic stabilities in rat plasma, liver and kidney homogenates, and extended pharmacokinetic profiles with the greater circulating half-lives (26.6, 64.5, and 105.5 min for Lys(34)-PEG(2,5,10 K)-GLP-1s, respectively, vs. 8.5 min for GLP-1, at elimination phases after i.p. injections) in ICR mice. Our findings suggest that GLP-1 substituted with a PEG of an appropriate Mw at Lys(34) could be used as a promising type 2 anti-diabetic agent to timely control postprandial glucose levels.
机译：快速消除胰高血糖素样肽-1（GLP-1）是其抗糖尿病作用的主要障碍。在这里，我们试图使用聚乙二醇化改善其不良的药代动力学/药效学特征。分别用2、5和10 kDa的PEG合成了位点特异性（Lys（34））PEG化的GLP-1。使用db / db小鼠进行的口服葡萄糖耐量测试显示，在腹腔内（ip）口服，口服30、30-120或120-360分钟时，这三种PEG化GLP-1（5 nmol / kg）可以特异性地稳定血浆葡萄糖水平， （总降血糖度：分别为60.5 +/- 5.0％，大约67.2 +/- 2.3％和大约59.4 +/- 4.3％）。尤其是，Lys（34）-PEG（10K）-GLP-1在给药长达360分钟的预葡萄糖后显示出稳定的降血糖功效。聚乙二醇化GLP-1的不同抗糖尿病作用归因于其增强的药代动力学和代谢抗性。这些类似物在大鼠血浆，肝和肾匀浆中具有更高的代谢稳定性，并且具有更长的循环半衰期（Lys（34）-PEG（2,5,10 K）-分别为26.6、64.5和105.5分钟）具有更长的药代动力学特征。在ICR小鼠中，GLP-1s在ip注射后消除阶段分别为GLP-1的8.5分钟和8.5分钟。我们的发现表明，在Lys（34）处用适当Mw的PEG取代的GLP-1可用作有前途的2型抗糖尿病药，以及时控制餐后血糖水平。

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