Three typical absorption enhancers, i.e., sodium caprate (Cap-Na), sodium deoxycholate (Deo-Na), and dipotassium glycyrrhizinate (Grz-K), were compared in terms of their permeability-enhancing effects on hydrophilic and hydrophobic model compounds in Caco-2 cell monolayers. The transepithelial electrical resistance (TEER) of the monolayers was reduced concentration-dependently by treatment with Cap-Na and Deo-Na, while treatment with Grz-K increased the TEER. Two patterns of TEER reduction were observed: one pattern indicated that Cap-Na had a rapid reducing effect, and another indicated that Deo-Na had a delayed reducing effect. These reductions in the TEER were accompanied by the increased transepithelial transport of two hydrophilic model compounds, sodium fluorescein (Flu-Na; MW = 376, log P = -1.52) and fluorescein isothiocyanate-dextran 4000 (FD-4; MW = 4400, log P = -2.0), and one hydrophobic model compound, rhodamine 123 hydrate (Rh123; MW = 381, log P = 1.13). The transport-enhancing effects of Cap-Na and Deo-Na on these model compounds decreased in the following order: FD-4 > Rh123 > Flu-Na, while Grz-K was found to have no effect on the transport of any of these model compounds. Confocal laser scanning microscopy (CLSM) of Caco-2 cell monolayers revealed that Cap-Na and Deo-Na enhanced the transepithelial transport of the hydrophilic model compounds via the paracellular route and that of the hydrophobic model compound via both paracellular and transcellular routes. Semiquantitative visual information obtained from CLSM images reflected the results of the transport experiment.

The absorption-enhancing effect of a combination of sodium deoxycholate and dipotassium glycyrrhizinate in Caco-2 cell monolayers has been compared with that of the enhancers when used alone, and the mechanism of the enhancement was partially elucidated. The effect of the combined compounds was evaluated by measurement of transepithelial electrical resistance (TEER) and the cellular permeability of the water-soluble model compounds sodium fluorescein (MW 376.3) and fluorescein isothiocyanate dextran (MW 4400). The TEER of the monolayers decreased with increasing concentrations of dipotassium glycyrrhizinate in combination with 0.02% (w/v) sodium deoxycholate for 20 min, and reached a minimum at 1% (w/v) dipotassium glycyrrhizinate. Although a combination of 0.02% (w/v) sodium deoxycholate and 1% (w/v) dipotassium glycyrrhizinate enhanced the cellular permeability of sodium fluorescein and fluorescein isothiocyanate dextran, 0.02% (w/v) sodium deoxycholate and 1% (w/v) dipotassium glycyrrhizinate alone had no effect on either the TEER of the monolayers or the cellular transport of the water-soluble compounds. Sequential and separate exposure of the monolayers to each enhancer for 10 min had no effect on the TEER, but a marked decrease in TEER was observed when both compounds were used in combination. The enhancing effect of the combination of sodium deoxycholate and dipotassium glycyrrhizinate was inhibited by H7, a protein kinase C (PKC) inhibitor, suggesting that dipotassium glycyrrhizinate might enhance the activation of PKC via sodium deoxycholate. The combined use of these two enhancers had no toxic effects. These results provide useful, basic information on the action of these absorption enhancers on drugs for which absorption is limited owing to polarity or molecular size, or both.

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The in vivo enhancing-activity of Grz in the absorption of drugs is dependent on GA, a hydrolysis product of Grz resulting from the action of beta-glucuronidase in intestinal flora.