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    Laurate permeates the paracellular pathway for small molecules in the intestinal epithelial cell model HT-29/B6 via opening the tight junctions by reversible relocation of claudin-5 (2014)

    Art
    Zeitschriftenartikel / wissenschaftlicher Beitrag
    Autoren
    Dittmann, I.
    Amasheh, M.
    Krug, S.M.
    Markov, A.G.
    Fromm, M.
    Amasheh, Salah (WE 2)
    Quelle
    Pharmaceutical research; 31(9) — S. 2539–2548
    ISSN: 0724-8741
    Sprache
    Englisch
    Verweise
    DOI: 10.1007/s11095-014-1350-2
    Pubmed: 24633418
    Kontakt
    Institut für Veterinär-Physiologie

    Oertzenweg 19 b
    14163 Berlin
    Tel.+49 30 838 62600 Fax.+49 30 838-62610
    email:physiologie@vetmed.fu-berlin.de

    Abstract / Zusammenfassung

    PURPOSE:
    To mechanistically analyze effects of the medium-chain fatty acid laurate on transepithelial permeability in confluent monolayers of the intestinal epithelial cell line HT-29/B6, in context with an application as an absorption enhancer improving transepithelial drug permeation.
    METHODS:
    Transepithelial resistance and apparent permeability for paracellular flux markers was measured using Ussing-type chambers. Two-path impedance spectroscopy was employed to differentiate between transcellular and paracellular resistance, and confocal imaging and Western blotting was performed.
    RESULTS:
    Laurate resulted in a substantial and reversible decrease in transepithelial resistance by 50% which was attributed to a decrease in paracellular resistance. Simultaneously, an increase in permeability for fluorescein (330 Da) was detected, while permeabilities for 4 kDa FITC-dextran and sulpho-NHS-SS-biotin (607 Da) remained unaltered. Confocal laser-scanning microscopy revealed a marked reduction of claudin-5, while other tight junction proteins including tricellulin, a protein preventing the paracellular passage of macromolecules, were not affected.
    CONCLUSIONS:
    Laurate induces an increase in paracellular permeability for molecules up to a molecular mass of 330 Da by retrieval of claudin-5 from tight junctions without affecting tricellular contacts and the paracellular passage of macromolecules. We hereby provide, for the first time, a mechanistical explanation of laurate-induced permeability enhancement on molecular level