THE CHALLENGE OF PROTEOLYTIC-ENZYMES IN INTESTINAL PEPTIDE DELIVERY

The former general belief that all peptides and proteins are entirely decomposed in the gastrointestinal tract before absorption occurs turn s out to be a misconception. Today several lines of evidence suggest t hat some proteins and peptides are capable of traversing the intestina l epithelium in intact form, however with yet unpredictable and often insufficient bioavailability, due to severe presystemic degradation in the gastrointestinal tract. Initial steps in the development of drug delivery systems for peroral peptide and protein administration involv e systematic case by case investigations on proteolytic degradation me chanisms and kinetics as well as segmental differences in degradation rate and intestinal permeability using a variety of techniques such as incubations with pancreatic enzymes, mucosal homogenates, brush-borde r membrane vesicles, intestinal rings and perfusion experiments. LHRH agonists, e.g. buserelin and immunoactive thymopoietin fragments are e xamples of compounds readily degraded by pancreatic trypsin, chymotryp sin and carboxypeptidases whereas metkephamid, a pentapeptide has been shown to completely resist proteases of pancreatic origin. Investigat ions on brush-border membrane-catalyzed degradation of several enkepha lin analogs demonstrate the versatility of the enzyme systems involved in the degradation and also the saturability of the reaction rate. Th e latter findings imply that at higher peptide doses (concentrations) the fraction absorbed can be expected to increase due to a saturabilit y of the degradation process. For proteolytically labile compounds, ap propriate means to stabilize the molecule within the gastrointestinal tract are mandatory in order to improve the fraction absorbed unchange d. These may involve a stabilization of the molecule itself, e.g. by i nserting unnatural D-amino acids into the molecule, N-methylation of p eptide bonds or cyclization, examples of which are presented. On the o ther hand, coadministration of protease inhibitors may significantly e nhance the bioavailability of a proteolytically labile peptide. A deli very system is presented which simultaneously releases a peptide toget her with an aminopeptidase inhibitor and a pH-modifier in the lower ga strointestinal tract, resulting in an improvement in absolute bioavail ability from 0.2% to 4%.