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

Abstract 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/C max 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.