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Titolo:
RAT JEJUNAL PERMEABILITY AND METABOLISM OF MU-SELECTIVE TETRAPEPTIDESIN GASTROINTESTINAL FLUIDS FROM HUMANS AND RATS
Autore:
KRONDAHL E; ORZECHOWSKI A; EKSTROM G; LENNERNAS H;
Indirizzi:
UPPSALA UNIV,DEPT PHARM,BOX 580,BMC S-75123 UPPSALA SWEDEN UPPSALA UNIV,DEPT PHARM S-75123 UPPSALA SWEDEN ASTRA PAIN CONTROL AB,DEPT DRUG METAB S-15185 SODERTALJE SWEDEN
Titolo Testata:
Pharmaceutical research
fascicolo: 12, volume: 14, anno: 1997,
pagine: 1780 - 1785
SICI:
0724-8741(1997)14:12<1780:RJPAMO>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
BRUSH-BORDER MEMBRANE; TRANSPORT-SYSTEM; CACO-2 CELLS; PEPTIDES; ABSORPTION; INHIBITION; INTESTINE; BESTATIN;
Keywords:
ENKEPHALIN ANALOGS; ORAL DRUG DELIVERY; PEPTIDE ABSORPTION; INTESTINAL PERFUSION; INTESTINAL METABOLISM; PROTEASE INHIBITORS;
Tipo documento:
Article
Natura:
Periodico
Citazioni:
25
Recensione:
Indirizzi per estratti:
Citazione:
E. Krondahl et al., "RAT JEJUNAL PERMEABILITY AND METABOLISM OF MU-SELECTIVE TETRAPEPTIDESIN GASTROINTESTINAL FLUIDS FROM HUMANS AND RATS", Pharmaceutical research, 14(12), 1997, pp. 1780-1785

Abstract

Purpose. To study intestinal transport and metabolism of three new mu-selective tetrapeptide enkephalin analogues, LEF537, LEF553 and TAPP. These peptides are stabilized against enzymatic hydrolysis by having a D-aminoacid in position 2 and a blocked COOH-terminal. Methods. We used a single-pass perfusion technique to study the transport of the peptides in rat jejunum. To reduce luminal and/or brush-border metabolism during the perfusion we used protease inhibitors (Pefabloc(R) SC, bestatin and thiorphan). The rate of metabolism was studied by incubations in rat jejunal homogenate, rat jejunal fluid and human gastric and jejunal fluid with and without these inhibitors. Results. The jejunal permeabilities (P-eff) of the peptides were 0.43-0.78.10(-4) cm/s without inhibitors and 0.09-0.45.10(-4) cm/s in presence of the inhibitors. All three peptides were rather rapidly degraded by enzymes in rat jejunal homogenate with half-lives of between 11.9 +/-: 0.5 and 31.7 +/-1.5 min. The addition of inhibitors to the homogenate prolonged the half-lives substantially for LEF553 (167 +/- 35 min) and TAPP (147 +/- 2 min), but only slightly for LEF537 (16.4 +/- 0.5 min). LEF553 and TAPP were both hydrolyzed in rat and human jejunal fluid, while LEF537 was metabolized less In these fluids. When LEF553 and TAPP were incubated with intestinal fluid in the presence of inhibitors, metabolism wasalmost completely inhibited. There was no metabolism for any of the peptides in human gastric juice. Conclusions. The replacement of the terminal free,carboxylic group with an amide group did not increase the stability of the peptides in jejunal tissue enough to allow successfuloral drug delivery.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/09/20 alle ore 09:25:51