{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T20:15:27Z","timestamp":1777580127680,"version":"3.51.4"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2000,7,1]],"date-time":"2000-07-01T00:00:00Z","timestamp":962409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2000,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The metabolism of three opioid tetrapeptides, Tyr-D-Arg-Phe-Nva-NH2, Tyr-D-Arg-Phe-Phe-NH2 and Tyr-D-Ala-Phe-Phe-NH2, was investigated in the presence of pure pancreatic enzymes (trypsin, chymotrypsin, elastase, carboxypeptidase A and carboxypeptidase B), as well as in the presence of pure carboxylesterase and aminopeptidase N. The cleavage patterns of the pure pancreatic enzymes were then compared with those found in rat and human jejunal fluid. Metabolism was also studied in homogenates from different intestinal regions (duodenum, jejunum, ileum and colon) and in enterocyte cytosol from rats. The effect of various protease inhibitors was investigated in the jejunal homogenate. The parent peptides were assayed by high-performance liquid chromatography and metabolites were identified by means of liquid chromatography-mass spectrometry.<\/jats:p>\n               <jats:p>Of the pure enzymes, the quickest hydrolysis of the peptides was observed for the pancreatic enzymes chymotrypsin, trypsin and carboxypeptidase A. In most cases they formed the corresponding deamidated tetrapeptides (chymotrypsin and trypsin) or tripeptides with a missing C-terminal amino acid (carboxypeptidase A). Regional differences in intestinal metabolism rates were found for all three peptides (P &amp;lt; 0.001), with the highest rates observed in jejunal and\/or colonic homogenates. The deamidated tetrapeptides were formed both in rat intestinal homogenates and in enterocyte cytosol. Metabolism in the jejunal homogenate was markedly inhibited by some serine and combined serine and cysteine protease inhibitors.<\/jats:p>\n               <jats:p>In conclusion, the C-terminal amide of these tetrapeptides did not fully stabilise them against intestinal deamidase and carboxypeptidase activities. The significant hydrolysis of the peptides by pure chymotrypsin, trypsin and carboxypeptidase A showed that lumenal pancreatic proteases might be a clear metabolic obstacle in oral delivery even for small peptides such as these tetrapeptides.<\/jats:p>","DOI":"10.1211\/0022357001774642","type":"journal-article","created":{"date-parts":[[2003,7,18]],"date-time":"2003-07-18T23:43:52Z","timestamp":1058571832000},"page":"785-795","source":"Crossref","is-referenced-by-count":13,"title":["Investigations of the In-vitro Metabolism of Three Opioid Tetrapeptides by Pancreatic and Intestinal Enzymes"],"prefix":"10.1093","volume":"52","author":[{"given":"Eva","family":"Krondahl","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Division of Pharmaceutics, Uppsala University , Box 580, BMC, SE-751 23 Uppsala,","place":["Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans","family":"Von Euler-Chelpin","sequence":"additional","affiliation":[{"name":"Preclinical Development, AstraZeneca R&D S\u00f6dert\u00e4lje , SE-151 85 S\u00f6dert\u00e4lje,","place":["Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Achim","family":"Orzechowski","sequence":"additional","affiliation":[{"name":"Preclinical Development, AstraZeneca R&D S\u00f6dert\u00e4lje , SE-151 85 S\u00f6dert\u00e4lje,","place":["Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gunilla","family":"Ekstr\u00f6m","sequence":"additional","affiliation":[{"name":"Preclinical Development, AstraZeneca R&D S\u00f6dert\u00e4lje , SE-151 85 S\u00f6dert\u00e4lje,","place":["Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans","family":"Lennern\u00e4s","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Division of Pharmaceutics, Uppsala University , Box 580, BMC, SE-751 23 Uppsala,","place":["Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2000,7,1]]},"reference":[{"key":"2024103110052680200_cit1","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1038\/45350","article-title":"A post-genomic challenge: learning to read patterns of protein synthesis","volume":"402","author":"Abbott","year":"1999","journal-title":"Nature"},{"key":"2024103110052680200_cit2","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1146\/annurev.ne.07.030184.001255","article-title":"Endogenous opioids: biology and function","volume":"7","author":"Akil","year":"1984","journal-title":"Ann. 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