Bridging the Gap between in vitro and in vivo Solubility-Permeability Interplay.

Use of solubilization carriers for poorly soluble drugs may disturb transmembrane absorption by lowering the activity of drug molecules, which is known as the solubility-permeability interplay. However, although many in vitro studies have indicated the negative impacts of use of solubilization carriers for oral absorption, in vivo studies that showed the interplay effect are limited. This study provides systematic in vitro, in situ, and in vivo investigation of the interplay effect of cyclodextrin using dexamethasone as a model drug. The evaluation methods included permeation through polymeric, artificial lipid, cell, and intestinal closed-loop membranes. Then, the results were compared with oral administration studies in mice and dogs. Although the interplay effect was clearly observed in the in vitro studies, no obvious interplay was found in the in vivo studies, suggesting that the interplay effect is more prominent in the in vitro permeation studies. Absence of in vivo interplay was attributed to the dilution effect in the gastrointestinal tract, interaction of the drug with living components, and clearance of the drug after membrane permeation. Overall, this investigation clearly demonstrated the applicability and limitations of in vitro permeation studies for predicting the interplay effects of solubilizers after the oral administration.