Little is known about the metabolism of the intestinotropic factor glucagon-like peptide-2 (GLP-2); except that it is a substrate for dipeptidyl peptidase IV (DPP-IV) and that it appears to be eliminated by the kidneys. We, therefore, investigated GLP-2 metabolism in six multicatheterized pigs receiving intravenous GLP-2 infusions (2 pmol/kg/min) before and after administration of valine-pyrrolidide (300 mumol/kg; a well characterized DPP-IV inhibitor). Plasma samples were analyzed by radioimmunoassays allowing determination of intact, biologically active GLP-2 and the DPP-IV metabolite GLP-2 (3-33). During infusion of GLP-2 alone, 30.9+/-1.7% of the infused peptide was degraded to GLP-2 (3-33). After valine-pyrrolidide, there was no significant formation of the metabolite. Significant extraction of intact GLP-2 was observed across the kidneys, the extremities (represented by a leg), and the splanchnic bed, resulting in a metabolic clearance rate (MCR) of 6.80+/-0.47 ml/kg/min and a plasma half-life of 6.8+/-0.8 min. Hepatic extraction was not detected. Valine-pyrrolidide addition did not affect extraction ratios significantly, but decreased (p=0.003) MCR to 4.18+/-0.27 ml/kg/min and increased (p=0.052) plasma half-life to 9.9+/-0.8 min. The metabolite was eliminated with a half-life of 22.1+/-2.6 min and a clearance of 2.07+/-0.11 ml/kg/min. In conclusion, intact GLP-2 is eliminated in the peripheral tissues, the splanchnic bed and the kidneys, but not in the liver, by mechanisms unrelated to DPP-IV. However, DPP-IV is involved in the overall GLP-2 metabolism and seems to be the sole enzyme responsible for N-terminal degradation of GLP-2.