Quantitative estimation of drug absorption in humans for passively transported compounds on the basis of their physico-chemical parameters

Good sigmoid relationships are found between human intestinal absorption fo r 32 passively transported drugs and their hydrogen bond descriptors. When only one-parameter correlations are considered, the sum of absolute H-bond acceptor and donor factor values (SigmaC(ad)), characterizing the total abi lity of a compound to form H-bonds, is the best descriptor. Such models sho w that H-bonding has a significant negative effect on human intestinal abso rption. Drugs with Sigma Cad greater than or equal to 22 are poorly absorbe d, while drugs with SigmaC(ad) less than or equal to 8 are completely absor bed. Such behavior may be rationalized by the beneficial influence that jus t a few H-bonding interactions might have on a drug's ability to penetrate biological membranes. Tn the case of many H-bonds, however, the penetration of a drug through a membrane may be completely forbidden. A two-parameter sigmoid model, where the sum of H-bond acceptor factors and the sum of H-bo nd donor factors are independent variables, demonstrates that both acceptor and donor groups on drugs have important interactions with surrounding wat er molecules or membrane surfaces. These models have improved statistical c riteria and ensure good quantitative predictions of human intestinal absorp tion for passively transported drugs. Polarizability makes a minor negative contribution while partial atomic charge makes a minor positive contributi on to absorption in humans. Lipophilicity expressed as logo did not give a satisfactory correlation with absorption.