Intrapulmonary potential of polyethylene glycol-modified glucagon-like peptide-1s as a type 2 anti-diabetic agent.

The pulmonary delivery of anti-diabetic peptide drugs can improve diabetic patient compliance. In this study, we tried to improve the pulmonary pharmacokinetic properties of glucagon-like peptide-1(7-36) (GLP-1) using a PEGylation approach. Initially, three types of site-specific (Lys(34)) PEGylated GLP-1 analogs were synthesized using PEGs of 2, 5, and 10 kDa, respectively. Their pharmacokinetic profiles were then examined in endotracheally cannulated rats. The results obtained show that all pharmacokinetic parameters (AUC(inf), C(max), t(1/2), V/F, and Cl/F etc.) of PEGylated GLP-1s were greatly improved by increasing PEG Mw. Specifically, the t(1/2) values of PEGylated GLP-1s (PEG Mw: 2, 5, 10 kDa) increased to 23.1+/-6.2, 41.6+/-12.3, and 81.7+/-11.7 min, respectively, vs. 8.9+/-2.9 min for intratracheally administered GLP-1. Also, PEGylated GLP-1s were found to have substantially greater C(max) values (7.4-7.8 ng/ml) than GLP-1 (4.0+/-2.4 ng/ml). Moreover, these PEGylated GLP-1s were found to have 10-20 fold more resistance to rat lung enzyme and plasma dipeptidyl peptidase IV (DPP IV). These findings indicate the dual-pharmacokinetic enhancements that PEGylated GLP-1s better survives proteolytic breakdown in the lungs than GLP-1s and better enters the systemic circulation, and that these analogs are more resistant to DPP IV-induced proteolysis and are much less rapidly removed from the systemic circulation. In conclusion, this study demonstrates the pharmaceutical usefulness of PEGylation in the context of the pulmonary delivery of GLP-1. These results show that PEGylated GLP-1s should be considered potential components of anti-diabetic inhalant preparations.