EFFECTS OF INCLUSION COMPLEXATION ON THE TRANSEPITHELIAL TRANSPORT OFA LIPOPHILIC SUBSTANCE IN-VITRO

Poor oral biovailability of three experimental compounds, I similar to III, observed in animals has been attributed to the low intrinsic sol ubility. To enhance their GI absorption, we attempted to increase the solubility of these compounds with hydroxypropyl beta-cyclodextrin (HP B)(4) and gamma-cyclodextrin (HPG). Compound I showed an increase in s olubility over 1,000-fold with 25% HPB at 25 degrees C. The associatio n constant of the 1:1 complex between I and HPB was determined by phas e-solubility analysis. Thermodynamic parameters involved were all favo rable for the complexation. The large positive Delta S degrees observe d suggests that the complex formation is driven by a hydrophobic inter action. Apical-to-basal transport of I across the Madin Darby canine k idney (MDCK) cell monolayer was studied at 37 degrees C in the presenc e of HPB with or without agitation. The complex itself did not pass th rough the cell layer. Diffusion of the unbound I as well as the comple x through the aqueous boundary layer in the apical side is rate-limiti ng. Regardless of hydrodynamics, decreasing HPB concentration at a giv en drug concentration increased the transport rate. The findings indic ate that the transepithelial transport is attributed to the passive di ffusion of available free drug molecules rather than the collision com plex transfer at the cell surface.