Quantitative Estimation of Drug Absorption in Humans for Passively Transported Compounds on the Basis of Their Physico-chemical Parameters

Abstract

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.

Rapid Prediction of Human Intestinal Absorption

“…There is a progressive decrease in the rate of absorption for a T values between 8 and 15 down to the point when the absorption is practically zero. In fact this region gives the characteristic sigmoidal shape for the plot, as has been described [2,5]. The experimental intestinal absorption shows a very similar dependence on the other applied hydrogen bond descriptor, HNOS T .…”

“…It is interesting to note that the sigmoidal relationship between HIA and the sum of acceptors and donors has been noted for 20 molecules by Palm et al [2] but the correlation was not significantly better than that between the number of acceptors and HIA. In a similar manner the sum of acceptor and donors was implicated in [5], although with the small number of molecules in that work (31 molecules), the individual donor and acceptor descriptors were found to be giving a better statistical description of HIA data. In the initial phase of this work, two procedures were applied to enumerate hydrogen bonds.…”

“…In previous works employing nonlinear functions, the data were fitted using sigmoidal functions based on exponential [4,5] or rational functions [2,15]. In contrast, the nonlinear terms in the QSAR equations in the current work were arctangent-based sigmoidals, as these were easier to handle.…”

Substrate recognition by P-glycoprotein efflux transporters: Structure-ATPase activity relationship of diverse chemicals and agrochemicals

“…Logit-transformed data for activities presented by % have been used previously in QSAR analyses. 27,28) First, the [logit A] values by the A-ring: 3,5-dimethyl and 2-Cl derivatives and non-substituted B-ring derivatives of DBHs were analyzed separately with CoMFA. Chromafenozide (21), 3,4-Me 2 (64), and 3,5-Cl 2 (67) compounds of the A-ring: 2-Cl derivatives were not included in the analyses because the activities produced by these compounds were measured at different concentrations from that by the other compounds.…”

Recent Advances in Computational Prediction of Drug Absorption and Permeability in Drug Discovery

“…w.x i + b +1, for y i = -1 class 2 (negative samples) (23) where y i is the class index, w is a vector normal to the hyperplane. After the determination of w and b, a given vector x i can be classified by: (24) In nonlinearly separable cases, SVM maps the input variable into a high-dimensional feature space using a kernel function K(x i , x j ).…”