Objective: To predict human intestinal
absorption and permeability coefficients in Caco-2 cell monolayers from net polar
atomic charges of drug molecules.Methods: The net atomic charges and the volumes of drug molecules were obtained with the semiempirical self-consistent field molecular orbital calculation CNDO/2 method and Mont Carlo method respectively,using the minimum energy conformation obtained from the optimization of the standard molecular geometry with the molecular mechanics MM+ method.The stepwise multiple regression analysis was used to obtain the correlation equations.Results: Both percent of human
intestinal absorption and permeability coefficients in Caco-2 cell monolayers of drug molecules were well correlated with the sum of the net atomic charges of all hydrogen-bonding donors(ΣQ_(H))and the sum of the net atomic charges of all hydrogen-bonding acceptors(ΣQ_(N,O)).The more the net positive atomic charges of hydrogen-bonding donors and the net negative atomic charges of hydrogen-bonding acceptors,the less were the percent human intestinal absorption and permeability coefficients in Caco-2 cell monolayers of drug molecules.Conclusion:
Drug absorption in human intestines is closely related with its hydrogen-bonding potential.The drug molecules with weaker hydrogen-bonding potential have greater percent human intestinal absorption.The net polar atomic charges can be computed simply,so they can be used in high throughput screening of oral drugs.