The pharmacokinetics and pharmacodynamics of progastrin-derived peptides

The elimination of progastrin-derived peptides was a first-order process, also at supraphysiological concentrations in plasma. The site of extraction was dependent on the molecular size of the peptides and not on their bioactivity. Apart from the kidneys and brain, where the extraction was nonselective, elimination was found in the gastrointestinal tract and limb (Gastrin-17, Gastrin-17 Gly and Gastrin-6). The porcine liver eliminated postprandial gastrin, while human gastrin except gastrin-6 passed unhindered. Metabolism of circulating gastrin was neither recorded in the lungs nor in the heart. In the kidneys peptides were mainly metabolized rather than excreted, since the recovery of intact peptide in urine was minimal. However, urinary clearance varied with the molecular form of the peptides under influence of glomerular filtration and handling in the renal tubules. Thus, N-terminal fragments had a higher urinary clearance than C-terminal peptides. Gastrin degrading enzymes were present in human and porcine plasma, but their contribution to whole-body metabolism was small. It is concluded that there is a differential metabolism of progastrin products in the vascular beds of which the integrated metabolism in nonorgan tissue such as limbs and trunk accounts for the major part of whole-body clearance.