Evaluation of dynamic polar molecular surface area as predictor of drug absorption: Comparison with other computational and experimental predictors

The relationship between various molecular descriptors and transport of dru gs across the intestinal epithelium was evaluated. The monolayer permeabili ty (P-c) of human intestinal Caco-2 cells to a series of nine beta-receptor -blocking agents was investigated in vitro. The dynamic polar molecular sur face area (PSA(d)) of the compounds was calculated from all low-energy conf ormations identified in molecular mechanics calculations in vacuum and in s imulated chloroform and water environments. For most of the investigated dr ugs, the effects of the different environments on PSA(d) were small. The ex ception was H 216/44, which is a large flexible compound containing several functional groups capable of hydrogen bonding (PSA(d,chloroform) = 70.8 An gstrom(2) and PSA(d,water) = 116.6 Angstrom(2)). The relationship between P -c and PSA(d) was stronger than those between P-c and the calculated octano l/water distribution coefficients (log D-calc) or the experimentally determ ined immobilized liposome chromatography (ILC) retention. P-c values for tw o new practolol analogues and H 216/44 were predicted from the structure-pe rmeability relationships of a subset of the nine compounds and compared wit h experimental values. The P-c values of the two practolol analogues were p redicted well from both PSA(d) calculations and ILC retention studies. The P-c value of H 216/44 was reasonably well-predicted only from the PSA(d) of conformations preferred in vacuum and in water. The other descriptors over estimated the P-c of H 216/44 100-500-fold.