Oral absorption of D-oligopeptides in rats via the paracellular route

This study was undertaken to examine the structural determinants of oral bioavailability in the rat of a set of oligopeptides comprising D-amino acids, which were taken to be absorbed paracellularly based on a pronounced sensitivity of permeability to electrical resistance in Caco-2 cell monolayers....

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Bibliographic Details
Published in:Pharmaceutical research 1996-11, Vol.13 (11), p.1673-1678
Main Authors: HE, Y.-L, MURBY, S, GIFFORD, L, COLLETT, A, WARHURST, G, DOUGLAS, K. T, ROWLAND, M, AYRTON, J
Format: Article
Language:English
Subjects:
Absorption
Administration, Oral
Animals
Biological and medical sciences
Biological Availability
Chromatography, High Pressure Liquid
Fundamental and applied biological sciences. Psychology
Intestine. Mesentery
Male
Molecular Weight
Oligopeptides - isolation & purification
Oligopeptides - pharmacokinetics
Oligopeptides - urine
Rats
Rats, Sprague-Dawley
Tritium
Vertebrates: digestive system
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Summary:This study was undertaken to examine the structural determinants of oral bioavailability in the rat of a set of oligopeptides comprising D-amino acids, which were taken to be absorbed paracellularly based on a pronounced sensitivity of permeability to electrical resistance in Caco-2 cell monolayers. The study series comprised eleven D-oligopeptides, designed not to be recognised by peptidases or transport proteins, and to have molecular weights between 222 and 406 daltons with different net electrical charges and composition of D-amino acids. All the peptides were [3H]-radiolabelled and analyzed by HPLC with radiometric detection. Bioavailability was estimated based on 24-hr urinary excretion of unchanged peptide after oral and intravenous administrations. As expected, the series proved metabolically stable. Bioavailability was independent of oral dose when varied by a factor of 10,000, suggesting passive absorption. Whereas bioavailability decreased sharply from 30% to 1% with increasing molecular weight, net charge showed little, if any, effect on bioavailability. This D-oligopeptide model series served as a useful probe for the structural requirements for paracellular absorption in vivo. A critical determinant of bioavailability is molecular size, expressed as molecular weight in this study; net charged appeared of much lesser importance.
ISSN:0724-8741
1573-904X
DOI:10.1023/A:1016440707092