TY - JOUR
T1 - Pharmacokinetic and pharmacodynamic evaluation of site-specific pegylated glucagon-like peptide-1 analogs as flexible postprandial-glucose controllers
AU - Chae, Su Young
AU - Chun, Goo Young
AU - Lee, Seulki
AU - Jin, Cheng Hao
AU - Lee, Eun Seong
AU - Lee, Kang Choon
AU - Youn, Yu Seok
N1 - Funding Information:
This work was supported by the Korean Research Foundation Grant funded by the “Korean Government (MOEHRD)” (#KRF-2006-353-E00022 to SY Chae), and the Ministry of Science and Technology of Korea (M10414030001-05N1403-00140).
PY - 2009/4
Y1 - 2009/4
N2 - 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-ls were synthesized with PEGs of 2, 5, and 10 kDa, respectively. Oral glucose tolerance tests using d6/d6 mice showed that these three PEGylated GLP-ls (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-PEGioK-GLP-l showed an stable hypoglycemic efficacy when administered up to 360 min preglucose. The different anti-diabetic effects of PEGylated GLP-ls 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-PEG2,5,10,K-GLP-ls, 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.
AB - 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-ls were synthesized with PEGs of 2, 5, and 10 kDa, respectively. Oral glucose tolerance tests using d6/d6 mice showed that these three PEGylated GLP-ls (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-PEGioK-GLP-l showed an stable hypoglycemic efficacy when administered up to 360 min preglucose. The different anti-diabetic effects of PEGylated GLP-ls 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-PEG2,5,10,K-GLP-ls, 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.
KW - Glucagon-like peptide-1
KW - Hypoglycemic efficacy
KW - Pegylation
KW - Pharmacokinetics
KW - Type 2 diabetes
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U2 - 10.1002/jps.21532
DO - 10.1002/jps.21532
M3 - Article
C2 - 18704955
AN - SCOPUS:67449164292
SN - 0022-3549
VL - 98
SP - 1556
EP - 1567
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
IS - 4
ER -