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

Yan Ling He, Susan Murby, Larry Gifford, Andrew Collett, Geoff Warhurst, Kenneth T. Douglas, Malcolm Rowland, John Ayrton

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Purpose. 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. Methods. 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. Results. 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. Conclusions. 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.

Original languageEnglish
Pages (from-to)1673-1678
Number of pages6
JournalPharmaceutical Research
Issue number11
Publication statusPublished - 1 Nov 1996
Externally publishedYes

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    He, Y. L., Murby, S., Gifford, L., Collett, A., Warhurst, G., Douglas, K. T., Rowland, M., & Ayrton, J. (1996). Oral absorption of D-oligopeptides in rats via the paracellular route. Pharmaceutical Research, 13(11), 1673-1678. https://doi.org/10.1023/A:1016440707092