Effects of inclusion complexation on the transepithelial transport of a lipophilic substance in vitro.

Poor oral bioavailability of three experimental compounds, 1-III, observed in animals has been attributed to the low intrinsic solubility. To enhance their GI absorption, we attempted to increase the solubility of these compounds with hydroxypropyl beta-cyclodextrin (HPB)4 and gamma-cyclodextrin (HPG). Compound I showed an increase in solubility over 1,000-fold with 25% HPB at 25 degrees C. The association constant of the 1:1 complex between I and HPB was determined by phase-solubility analysis. Thermodynamic parameters involved were all favorable for the complexation. The large positive delta S degrees observed suggests that the complex formation is driven by a hydrophobic interaction. Apical-to-basal transport of I across the Madin Darby canine kidney (MDCK) cell monolayer was studied at 37 degrees C in the presence of HPB with or without agitation. The complex itself did not pass through the cell layer. Diffusion of the unbound I as well as the complex through the aqueous boundary layer in the apical side is rate-limiting. Regardless of hydrodynamics, decreasing HPB concentration at a given drug concentration increased the transport rate. The findings indicate that the transepithelial transport is attributed to the passive diffusion of available free drug molecules rather than the collision complex transfer at the cell surface.