CORRELATION OF DRUG ABSORPTION WITH MOLECULAR-SURFACE PROPERTIES

The correlation between dynamic surface properties of drug molecules a nd drug absorption in two common in vitro models of the intestinal wal l (Caco-2 monolayers and rat intestinal segments) has been investigate d. A homologous series of P-adrenoreceptor antagonists were used as mo del compounds. Dynamic molecular surface properties, considering all l ow-energy conformations, of the compounds were calculated. The flexibi lity of the molecules was studied by molecular mechanics calculations (MM2) and the van der Waals' (vdW), and water accessible surface areas were calculated and averaged according to a Boltzmann distribution. E xcellent correlations were obtained between the dynamic polar vdW surf ace areas and cell permeabilities in Caco-2 cells and rat ileum (r(2) = 0.99 and 0.92, respectively). These correlations were stronger than those between calculated octano/buffer partition coefficients (log D-o ct,D-7.4) and permeability (r(2) = 0.80 and 0.73, respectively). Moreo ver, the calculated log D-oct,D-7.4 values failed to rank the permeabi lity coefficients through Caco-2 monolayers and rat ileum in the corre ct order. The results indicate that dynamic polar surface area is a pr omising alternative model for the prediction of oral drug absorption.