Glucagon-like peptide-1(7–37) has a larger volume of distribution than glucagon-like peptide-1(7–36)amide in dogs and is degraded more quickly in vitro by dog plasma

Abstract

The pharmacokinetic properties of glucagon-like peptide-1(7–36)amide and GLP-1(7–37) were compared. Four beagle dogs received on 4 separate occasions s.c. bolus doses of 50 μg/kg, and 2 min i.v. infusions of 50μg/kg of each peptide. The plasma immunoreactivity of GLP-1 (P-GLP-1-IR) was measured by a sandwich enzyme-linked immunosorbent assay (ELISA). After i.v. infusion, the plasma half-life in the first-phase was 2.1±0.1 and 2.4±0.3 min, in the final-phase 68±6 and 81±3 min, the total plasma clearance 25±3 and 22±4 ml/kg. min, the volume of distribution at steady state 0.16±0.02 and 0.84±0.24 l/kg, and the mean residence time 6.2±0.3 and 36±5 min for GLP-1(7–36)amide and GLP-1(7–37), respectively. After s.c. administration, the maximum plasma concentration was reached after 15±5 and 19±4 min and the absolute bioavailability was 48±7 and 49±13% for GLP-1(7–36)amide and GLP-1(7–37), respectively. P-GLP-1-IR, measured by a radioimmunoassay (RIA), was considerably higher than when measured by ELISA. This discrepancy was due to cross-reactivity with metabolites of the parent peptide. The plasma degradation was studied in vitro in dog plasma at 37°C, and the half-lives were found to be 61±9 and 132±16 min for GLP-1(7–36)amide and GLP-1(7–37), respectively (n=6). Bacitracin inhibited the degradation of both peptides.