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• W2011229128 abstract "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 (Lys34) 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%, ∼67.2 ± 2.3%, and ∼59.4 ± 4.3%, respectively). Particularly, Lys34-PEG10K-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 Lys34-PEG2,5,10 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 Lys34 could be used as a promising type 2 anti-diabetic agent to timely control postprandial glucose levels. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:1556–1567, 2009" @default.
• W2011229128 created "2016-06-24" @default.
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• W2011229128 date "2009-04-01" @default.
• W2011229128 modified "2023-09-26" @default.
• W2011229128 title "Pharmacokinetic and pharmacodynamic evaluation of site-specific PEGylated glucagon-like peptide-1 analogs as flexible postprandial-glucose controllers" @default.
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• W2011229128 doi "https://doi.org/10.1002/jps.21532" @default.
• W2011229128 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/18704955" @default.
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