POLAR MOLECULAR-SURFACE PROPERTIES PREDICT THE INTESTINAL-ABSORPTION OF DRUGS IN HUMANS

Purpose. A theoretical method has been devised for prediction of drug absorption after oral administration to humans. Methods. Twenty struct urally diverse model drugs, ranging from 0.3 to 100% absorbed, were in vestigated. The compounds also displayed diversity in physicochemical properties such as lipophilicity, hydrogen bonding potential and molec ular size. The dynamic molecular surface properties of the compounds w ere calculated, taking into account their three-dimensional shape and flexibility. Results. An excellent sigmoidal relationship was establis hed between the absorbed fraction after oral administration to humans (FA) and the dynamic polar molecular surface area (PSA(d)) (r(2) = 0.9 4). The relationship was stronger than those obtained for more establi shed predictors of drug absorption. Drugs that are completely absorbed (FA > 90%) had a PSA(d) less than or equal to 60 Angstrom(2) while dr ugs that are < 10% absorbed had a PSA(d) greater than or equal to 140 A(2). Conclusions. The results indicate that PSA(d) can be used to dif ferentiate poorly absorbed drugs at an early stage of the drug discove ry process.