Good sigmoid relationships are found between human intestinal absorption for 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 (SC ad ), characterizing the total ability of a compound to form H-bonds, is the best descriptor. Such models show that H-bonding has a signi®cant negative effect on human intestinal absorption. Drugs with SC ad ! 22 are poorly absorbed, while drugs with SC ad 8 are completely absorbed. Such behavior may be rationalized by the bene®cial in¯uence that just a few H-bonding interactions might have on a drug's ability to penetrate biological membranes. In 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-bond donor factors are independent variables, demonstrates that both acceptor and donor groups on drugs have important interactions with surrounding water molecules or membrane surfaces. These models have improved statistical criteria and ensure good quantitative predictions of human intestinal absorption for passively transported drugs. Polarizability makes a minor negative contribution while partial atomic charge makes a minor positive contribution to absorption in humans. Lipophilicity expressed as log D did not give a satisfactory correlation with absorption.
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