[Prediction of human intestinal absorption from net polar atomic charges of drug molecules].
To predict human intestinal absorption and permeability coefficients in Caco-2 cell monolayers from net polar atomic charges of drug molecules.



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.



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 (sigmaQH) and the sum of the net atomic charges of all hydrogen-bonding acceptors (sigmaQN, 0). 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.



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.
Fu
Xu-chun
XC
Department of Pharmacy, Zhejiang University City College, Hangzhou 310015, China. fuxc@zucc.edu.cn
Zhan
Shu-yu
SY
D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000502:physiology; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000502:physiology; D006801:Humans; D006860:Hydrogen Bonding; D007408:Intestinal Absorption; D008956:Models, Chemical; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D012044:Regression Analysis
D000319:Adrenergic beta-Antagonists; D004364:Pharmaceutical Preparations