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Titolo:
Stability and in vitro metabolism of dipeptide model prodrugs with affinity for the oligopeptide transporter
Autore:
Lepist, EI; Kusk, T; Larsen, DH; Andersen, D; Frokjaer, S; Taub, ME; Veski, P; Lennernas, H; Friedrichsen, G; Steffansen, B;
Indirizzi:
Royal Danish Sch Pharm, DK-2100 Copenhagen, Denmark Royal Danish Sch Pharm Copenhagen Denmark DK-2100 00 Copenhagen, Denmark Univ Tartu, Dept Pharm, EE-51014 Tartu, Estonia Univ Tartu Tartu EstoniaEE-51014 u, Dept Pharm, EE-51014 Tartu, Estonia Novo Nordisk AS, DK-2760 Maaloev, Denmark Novo Nordisk AS Maaloev Denmark DK-2760 isk AS, DK-2760 Maaloev, Denmark Univ Uppsala, Dept Pharmaceut, S-75123 Uppsala, Sweden Univ Uppsala Uppsala Sweden S-75123 Pharmaceut, S-75123 Uppsala, Sweden
Titolo Testata:
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
fascicolo: 1, volume: 11, anno: 2000,
pagine: 43 - 50
SICI:
0928-0987(200007)11:1<43:SAIVMO>2.0.ZU;2-J
Fonte:
ISI
Lingua:
ENG
Soggetto:
PEPTIDE TRANSPORTER; INTESTINAL-ABSORPTION; CACO-2 MONOLAYERS; DRUG-DELIVERY; D-ASP(OBZL)-ALA; PERMEABILITY; HYDROLYSIS; CELLS;
Keywords:
prodrug; oligopeptide transporter; dipeptide; stability; in vitro metabolism;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
22
Recensione:
Indirizzi per estratti:
Indirizzo: Steffansen, B Royal Danish Sch Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark Royal Danish Sch Pharm Univ Pk 2 Copenhagen Denmark DK-2100
Citazione:
E.I. Lepist et al., "Stability and in vitro metabolism of dipeptide model prodrugs with affinity for the oligopeptide transporter", EUR J PH SC, 11(1), 2000, pp. 43-50

Abstract

One approach to increase drug stability and to facilitate oral absorption of low bioavailability drugs may be to design oligopeptide ester prodrugs which are stable in the gastrointestinal tract, are transported via the oligopeptide transporter, and finally release the parent drug molecule into theblood circulation and/or by its site of action. In these kinds of prodrugsthe ester linkage may be broken by pH dependent and/or enzyme catalyzed hydrolysis. The objective of the present study was to investigate the degradation mechanism and rate of the model compounds Glu(OBzl)-Sar, D-Glu(OBzl)-Ala and Asp(OBzl)-Sar in aqueous solution and in relevant biological media and to compare these results with those of our previous study of D-Asp(OBzl)-Ala. Furthermore, the resulting aqueous stability and in vitro metabolism data are related to our previous affinity data to evaluate if Glu-Sar, D-Glu-Ala, and Asp-Sar have potential as pro-moieties in these kinds of prodrugs. The degradation rates follow first-order kinetics, show maximum stability at pH 4-5 with maximum half-lives for Asp(OBzl)-Sar, Glu(OBzl)-Sar, and D-Glu(OBzl)-Ala of 115 h, 30 days and 152 days, respectively. The stability was dependent on buffer concentration, temperature, pH, and ionic strength. In biological media such as 80% human plasma, human gastric juice and intestinal fluid, and 10% rat jejunal homogenate at 37 degrees C, the half-lives were greater than 1 h except for the hydrolysis of Glu(OBzl)-Sar in 10% rat jejunal homogenate, where the half-life was approximately 16 min. All the stabilized dipeptides may have potential as drug carriers targeting hPepT1. (C) 2000 Elsevier Science B.V. All rights reserved.

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Documento generato il 07/04/20 alle ore 22:53:28