Penetration and enzymatic barriers to peptide and protein absorption

Abstract The recent rise to prominence of therapeutic peptides and proteins as potential drugs of the future, coupled with their oral ineffectiveness due to proteolytic destruction, has focused attention on non-oral routes for routine drug administration. Although there was early optimism about these routes, the bioavailability of peptides and proteins from the non-oral mucosal routes is, in reality, poor when compared with the parenteral route, because of the formidable penetration and enzymatic barriers to mucosal peptide and protein absorption. The purpose of this review is twofold: (1) to describe the nature and magnitude of the penetration and enzymatic barriers to peptide and protein drug absorption, and (2) to review critically the effectiveness and limitations of the approaches that have been used to overcome such barriers.