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

The pharmacokinetic properties of glucagon-like peptide-1(7-36)amide ( GLP-1(7-36)amide) and GLP-1(7-37) were compared. Four beagle dogs rece ived on 4 separate occasions s.c. bolus doses of 50 mu g/kg, and 2 min i.v. infusions of 50 mu g/kg of each peptide. The plasma immunoreacti vity of GLP-1(P-GLP-1-IR) was measured by a sandwich enzyme-linked imm unosorbent 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-pha se 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 reach ed after 15 +/- 5 and 19 +/- 4 min and the absolute bioavailability wa s 48 +/- 7 and 49 +/- 13% for GLP-1(7-36)amide and GLP-1(7-37), respec tively. P-GLP-1-IR, measured by a radioimmunoassay (RIA), was consider ably higher than when measured by ELISA. This discrepancy was due to c ross-reactivity with metabolites of the parent peptide. The plasma deg radation was studied in vitro in dog plasma at 37 degrees C, and the h alf-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.