Modulation of Tight Junctions does Not Predict Oral Absorption of Hydrophilic Compounds: Use of Caco-2 and Calu-3 Cells

다국어 초록 (Multilingual Abstract)

Permeability estimates using Caco-2 cells do not accurately predict the absorption of hydrophilic
drugs that are primarily absorbed via the paracellular pathway. The objective of this study
was to investigate whether modulation of tight junctions would help differentiation of paracellularly
absorbed compounds. Tight junctions in Caco-2 cell monolayers were manipulated using
calcium depletion approaches to decrease the transepithelial electrical resistance (TEER) of
the monolayers, and permeability of hydrophilic compounds were measured under these conditions.
Permeability of these compounds were also measured in Calu-3 cells, which have
tighter junctions than Caco-2 cells. Calcium depletion loosened the tight junctions of Caco-2
cells to varying levels as measured by the decrease in TEER values of the monolayers. While
the absolute permeability of all the model compounds increased as the tight junctions were
loosened, the ratios of their permeability relative to mannitol permeability were similar. The permeability
of these compounds in the tighter Calu-3 cells were also found to be similar to each
other. Altering the tight junctions of Caco-2 cells to obtain leakier cell monolayers, or using a
cell line with tighter junctions like Calu-3 cells, did not improve differentiation between well
absorbed and poorly absorbed hydrophilic drugs. Mere manipulation of the tight junctions to
increase or decrease transepithelial electrical resistance does not appear to be a viable
approach to predict human absorption for hydrophilic compounds that are primarily absorbed
via the paracellular pathway.

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