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 drugs across the intestinal epithelium was evaluated. The monolayer permeability (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 surface area (PSA(d)) of the compounds was calculated from all low-energy conformations identified in molecular mechanics calculations in vacuum and in simulated chloroform and water environments. For most of the investigated drugs, the effects of the different environments on PSA(d) were small. The exception was H 216/44, which is a large flexible compound containing several functional groups capable of hydrogen bonding (PSA(d,chloroform) = 70.8 Angstrom(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 octanol/water distribution coefficients (log D-calc) or the experimentally determined immobilized liposome chromatography (ILC) retention. P-c values for two new practolol analogues and H 216/44 were predicted from the structure-permeability relationships of a subset of the nine compounds and compared with experimental values. The P-c values of the two practolol analogues were predicted 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 overestimated the P-c of H 216/44 100-500-fold.