Influences of regional differences in activities of brush-border membrane peptidases within the rat intestine on site-dependent stability of peptide drugs.

Proteolytic hydrolysis rates of neurotensin and acetyl-neurotensin-(8-13) by brush-border membranes from various rat intestinal segments were as follows: jejunum > duodenum approximately jejunoileal junction > ileum > caecum. The rank order of endopeptidase-24.11 activity along the intestine was jejunum > duodenum approximately jejunoileal junction > ileum > caecum. Angiotensin converting enzyme (ACE) had a similar distribution profile as endopeptidase-24.11. Activities of these two enzymes were lower in the distal intestine. Distribution of endopeptidase-2 activity along the intestine was different: ileum > duodenum approximately jejunum approximately jejunoileal junction > caecum. The profiles of differential hydrolysis of neurotensin and acetylneurotensin-(8-13) within the gut corresponded to the distribution of endopeptidase-24.11 and ACE. Moreover, effects of enzyme inhibitors confirm that these two enzymes initiated proteolysis of neurotensin and acetylneurotensin-(8-13). These results suggest that the regional differences in the activities of key brush-border membrane peptidases will affect site-dependent stability of peptide drugs.