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.
Bai
J P
JP
College of Pharmacy, University of Minnesota, Minneapolis 55455.
D000818:Animals; D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D010450:Endopeptidases / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000648:ultrastructure*; D008297:Male; D008871:Microvilli / Q000201:enzymology*; D008969:Molecular Sequence Data; D009496:Neurotensin / Q000031:analogs & derivatives / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity
D010455:Peptides; D009496:Neurotensin; D010450:Endopeptidases