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Oligonucleotide transport in rat and human intestine Ussing chamber models
Author(s) -
WuPong Susanna,
Livesay Virginia,
Dvorchik Barry,
Barr William H.
Publication year - 1999
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/1099-081x(199912)20:9<411::aid-bdd208>3.0.co;2-4
Subject(s) - paracellular transport , ussing chamber , transcellular , biophysics , absorption (acoustics) , biology , fluorescein isothiocyanate , intestinal mucosa , fluorescein , biochemistry , microbiology and biotechnology , in vitro , chemistry , fluorescence , medicine , membrane , permeability (electromagnetism) , acoustics , physics , quantum mechanics
Abstract Cellular and intestinal absorption of naked oligonucleotides (ONs) is limited and still remains a developmental challenge. A previous report in the literature suggests that ON absorption occurs via a paracellular mechanism. The aim of this study was to test this hypothesis using rat and human intestine in a Ussing chamber and in Caco‐2 cells. Transport of a 35 S‐labelled mixed backbone ON (MBO) across human or rat intestinal tissue or across Caco‐2 cells was measured after a 2‐h incubation in the presence or absence of increasing MBO concentrations or with uptake inhibitors and enhancers. MBO intestinal absorption was compared with an internal standard, mannitol. 35 S‐MBO demonstrated very little absorption (<1%) across rat and human intestinal tissues. Transport appeared to be unsaturable up to 500 μM, and relatively insensitive to compounds that opened tight junctions or inhibited P‐glycoprotein. However, preliminary studies with Caco‐2 cells suggest a possible saturable mechanism at higher ON concentrations. Confocal fluorescence microscopy studies show that fluorescein isothiocyanate (FITC)‐MBO was internalized into intestinal cells. Although some differences in ON transport were observed as a function of the transport model, MBO transport was mostly consistent with a transcellular, rather than a paracellular, absorption mechanism. Copyright © 1999 John Wiley & Sons, Ltd.