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Vol. 284, Issue 1, 362-369, 1998
Department of Pharmacy, Division of Pharmaceutics, Uppsala
University, Sweden
Medium chain fatty acids (MCFAs) are used to enhance the permeability
of mucosal tissues to hydrophilic drugs, but their mechanism of action
is largely unknown. In this study, the absorption-enhancing effects of
the sodium salts of two MCFAs, capric acid (C10) and lauric acid (C12),
were studied in monolayers of human intestinal epithelial Caco-2 cells.
Both MCFAs induced a rapid increase in epithelial permeability to the
hydrophilic marker molecule sodium fluorescein. Inhibition of
phospholipase C and inhibition or activation of various kinases and
buffering of intracellular calcium indicated that the effects on
epithelial permeability were mediated through phospholipase C-dependent
inositol triphosphate/diacylglycerol pathways. Surprisingly, the
inositol triphosphate and diacylglycerol pathways were found to have
opposing effects on paracellular permeability. Exposure to the MCFAs
also resulted in a concentration dependent reduction of cellular
dehydrogenase activity and ATP levels. C10, but not C12, induced
redistribution of the tight junction proteins ZO-1 and occludin. These
results indicate that the two MCFAs have partially different and more
complex mechanisms than previously recognized, which has important
implications for their use in vivo.
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