Pharmacokinetic actions of exendin-4 in the rat: Comparison with glucagon-like peptide-1

Exendin-4, originally isolated from saliva of the lizard Heloderma suspectum, shares 53% sequence homology and several potentially antidiabetic actions with the mammalian hormone glucagon-like peptide-1(7-36)amide (GLP-1). It shows a higher potency and longer duration of effect in vivo, which may be partly attributed to pharmacokinetic properties. The present study compares the pharmacokinetics of GLP-1 and exendin-4 in rats after intravenous (iv), subcutaneous (sc), or intraperitoneal (ip) administration. Samples were assayed for active GLP-1 (7-36) amide using an enzyme-linked immunosorbent assay that does not detect GLP-1 (1-36-amide), (1-37), (9-36-amide) or (9-37). In parallel experiments, samples were assayed for exendin-4 using a two-site immunoradiometric assay that reacts specifically with full-length exendin-4. The estimated half-life for GLP-1 and exendin-4 were 0.8–4.7 min and 18–41 min for iv bolus, and 4.6–7.1 min and 90–216 min for SC administration, respectively. Half-lives after ip injection were 0.6–13.5 min for GLP-1 and 125–174 min for exendin-4. Bioavailability for GLP-1 and exendin-4 was 44–71% and 65–75%, respectively, for sc injection. For ip injection, bioavailability for GLP-1 and exendin-4 was 36–67% and 74–76%, respectively. Plasma clearance, as determined from iv infusion data, was 35–38 ml/min for GLP-1 and 4-8 ml/min for exendin-4. Both Co/Cmax and AUC values were proportional to dose with each route of administration. Plasma clearance of exendin-4 was reduced by 4.4-fold in nephrectomized animals. In conclusion, exendin-4 exhibited a much longer plasma half-life than GLP-1 in rats after iv, sc, or ip injection, which may contribute in some part to reported differences in duration of biological action of the two peptides. Drug Dev. Res. 53:260–267, 2001. © 2001 Wiley-Liss, Inc.