title: Pharmacokinetic and pharmacodynamic evaluation of site-specific PEGylated glucagon-like peptide-1 analogs as flexible postprandial-glucose controllers.
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 (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.
authors.affiliation: College of Pharmacy, SungKyunKwan University, Suwon City 440-746, Korea. ysyoun@pusan.ac.kr
authors.forename: Su Young
authors.initials: SY
authors.lastname: Chae
authors.forename: Young Goo
authors.initials: YG
authors.lastname: Chun
authors.forename: Seulki
authors.initials: S
authors.lastname: Lee
authors.forename: Cheng-Hao
authors.initials: CH
authors.lastname: Jin
authors.forename: Eun Seong
authors.initials: ES
authors.lastname: Lee
authors.forename: Kang Choon
authors.initials: KC
authors.lastname: Lee
authors.forename: Yu Seok
authors.initials: YS
authors.lastname: Youn
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D010446:Peptide Fragments / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry*; D019518:Postprandial Period; D011485:Protein Binding; D051381:Rats
chemical_list: D001786:Blood Glucose; D004337:Drug Carriers; D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments; C055453:glucagon-like peptide 1 (7-36)amide; D011092:Polyethylene Glycols; D052216:Glucagon-Like Peptide 1; C028210:monomethoxypolyethylene glycol