A GENERAL-APPROACH FOR THE PREDICTION OF THE INTESTINAL-ABSORPTION OFDRUGS - REGRESSION-ANALYSIS USING THE PHYSICOCHEMICAL PROPERTIES AND DRUG-MEMBRANE ELECTROSTATIC INTERACTION

A general method for predicting the intestinal absorption of a wide ra nge of drugs using multiple regression analysis of their physicochemic al properties and the drug-membrane electrostatic interaction was deve loped. The absorption rates of tested drugs from rat jejunum were meas ured by the in situ single-pass perfusion technique. The drugs used in this study were divided into three groups for regression analysis, an d a smaller ''test'' set of compounds was used to assess the predictiv e capacity of the regression equation. When the analysis was applied t o each respective group of drugs (i.e., anionic, cationic, and nonioni zed compounds), obtained regression coefficients were 0.569, 0.821, 0. 728 by using the organic solvent (n-octanol)/buffer partition coeffici ent, 0.730, 0.734, 0.914 using the permeation rate across a silicon me mbrane, and 0.790, 0.915, 0.941 using an EVA membrane, respectively. H owever, smaller regression coefficients of 0.377, 0.468, and 0.718 wer e obtained when these three groups of drugs were put together for pred iction. Meanwhile, correlation was improved remarkably when drug-membr ane electrostatic interactions, namely, hydrogen-bonding donor (H-alph a) and acceptor (H-beta) activity or index of electricity (E-c), were added to the other parameters of lipophilicity and permeation rate acr oss the EVA membrane (r = 0.880 and 0.883, respectively). Moreover, th e equation obtained from these regression analyses was applicable even to the prediction of the absorption of the zwitterionic drugs. These results suggest that including the electrostatic interaction parameter s in addition to lipophilicity and permeability across artificial memb ranes would afford a better prediction for the intestinal absorption o f the vast majority of drugs.