EFFECTIVENESS AND TOXICITY SCREENING OF VARIOUS ABSORPTION ENHANCERS USING CACO-2 CELL MONOLAYERS

We studied the enhancing and toxic effects of five different absorptio n enhancers on the transport of FITC-dextran with an average molecular weight of 4000 (FD-4) across Caco-2 cell monolayers, and their enhanc ing effects were also compared with those in rat intestine. The enhanc ing and cytotoxic properties of these enhancers were characterized usi ng the following tests: measurement of the permeability coefficients o f FD-4 and the transepithelial electrical resistance (TEER) in Caco-2, the release of cytosolic lactate dehydrogenase (LDH) and intracellula r mitochondrial dehydrogenase (MDH) activity. All the absorption enhan cers increased the permeability of FD-4 across Caco-2 cell monolayers and a good relationship was observed between the enhancement and their toxic effects. However, EDTA and Na-Cap were effective for improving the transport of FD-4 across Caco-2 cells without serious cytotoxicity , At concentrations with low cytotoxicity, various absorption enhancer s exihibited reversible effects on the TEER values in Caco-2 cell mono layers, except for 50 mM sodium salicylate (Na-Sal), Moreover, we obta ined a good correlation between the enhancement of these enhancers in Caco-2 cell monolayers and in rat large intestine. This finding indica ted that the effectiveness of absorption enhancers in the Caco-2 monol ayer system was similar to an irt vivo rat system, Therefore, the scre ening system using Caco-2 cell monolayers is useful for examining the effectiveness and toxicity of absorption enhancers.