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Titolo:
Investigations of the in-vitro metabolism of three opioid tetrapeptides bypancreatic and intestinal enzymes
Autore:
Krondahl, E; Von Euler-Chelpin, H; Orzechowski, A; Ekstrom, G; Lennernas, H;
Indirizzi:
Uppsala Univ, Div Pharmaceut, Dept Pharm, SE-75123 Uppsala, Sweden UppsalaUniv Uppsala Sweden SE-75123 ept Pharm, SE-75123 Uppsala, Sweden AstraZeneca R&D Sodertalje, Preclin Dev, SE-15185 Sodertalje, Sweden AstraZeneca R&D Sodertalje Sodertalje Sweden SE-15185 Sodertalje, Sweden
Titolo Testata:
JOURNAL OF PHARMACY AND PHARMACOLOGY
fascicolo: 7, volume: 52, anno: 2000,
pagine: 785 - 795
SICI:
0022-3573(200007)52:7<785:IOTIMO>2.0.ZU;2-2
Fonte:
ISI
Lingua:
ENG
Soggetto:
LYSOSOMAL PROTECTIVE PROTEIN; ACTING ENKEPHALIN ANALOGS; RAT INTESTINE; LEUCINE-ENKEPHALIN; PEPTIDE; ABSORPTION; PERMEABILITY; INHIBITORS; CHALLENGE; STABILITY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
37
Recensione:
Indirizzi per estratti:
Indirizzo: Lennernas, H Uppsala Univ, Div Pharmaceut, Dept Pharm, Box 580,BMC, SE-75123 Uppsala, Sweden Uppsala Univ Box 580,BMC Uppsala Sweden SE-75123 ala, Sweden
Citazione:
E. Krondahl et al., "Investigations of the in-vitro metabolism of three opioid tetrapeptides bypancreatic and intestinal enzymes", J PHARM PHA, 52(7), 2000, pp. 785-795

Abstract

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 pancreaticenzymes 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. Of the pure enzymes, the quickest hydrolysis of the peptides was observed for the pancreatic enzymes chymotrypsin, trypsin and carboxypeptidase A. Inmost 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 < 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. 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/09/20 alle ore 10:39:20