Predominance of renal and absence of hepatic metabolism of pancreatic polypeptide in the dog

Pancreatic polypeptide (PP) metabolism was studied in the dog. Metabolic clearance rate (MCR) of PP was found to be 9.5 +/- 0.9 ml . kg-1 . min-1, accounted for predominantly by renal extraction (34.9 +/- 2.6% of exogenous PP), which comprised 45.5 +/- 5.8% of total PP clearance. Hepatic extraction of both endogenous (-9.9 +/- 6.1%) and exogenous (2.2 +/- 1.4%) PP infused to pharmacological levels was negligible, as was its splanchnic extraction (4.2 +/- 0.9%). Renal organ clearance of exogenous PP (3.7 +/- 0.3 ml . kg-1 . min-1) closely approximated that of inulin (3.6 +/- 0.3 ml . kg-1 . min-1), indicating that renal PP metabolism occurs entirely by glomerular filtration without contribution from peritubular uptake mechanisms. Urinary PP, chromatographically indistinguishable from that in plasma but quantitatively accounting for less than 1% of overall renal PP uptake, indicated virtually complete renal degradation of the peptide to nonimmunoreactive fragments. Renal PP extraction was shown to be nonsaturable. Plasma half disappearance time of PP was 10.1 +/- 1.0 min and apparent distribution space 307 +/- 39 ml/kg. Linkage between the hepatic action and degradation of insulin and glucagon has been proposed, and in this light absent hepatic PP extraction is noteworthy. This finding, reminiscent of the hepatic handling of metabolically inert C-peptide and biologically inactive glucagon peptides, is consistent with the absence of demonstrable physiological function of PP.