Quantitative structure‐activity relationships: Molecular structures and different modes of exposure affecting transport and toxicities of chemicals: QSAR analysis

Abstract

AbstractAlthough relatively few systematic studies have been reported on the disposition of various toxicants or pollutants, considerable effort has been devoted to disposition studies on various drugs and simple organic molecules. Our group and others have in the last few years reported the quantitative structure‐activity relationships (QSAR) on the absorption, distribution and metabolism of several series of organic compounds. The mathematical model embodies the concept of the pH partition hypothesis and the Sutherland‐Einstein diffusion equation, as well as Hansch's parabolic model. For most exogenous molecules of intermediate mol wt (102 to 104), passive diffusion through the lipoprotein barrier appears to be the most important route among the known mechanisms of absorption, with an ideal lipophilic character (log P0) around 0.5 to 3. For polar and/or high mol wt compounds (>104) passage through interstitial space becomes mainly a negative function of log mol wt. High mol wt compounds and strong acids and bases (highly ionized) should not be absorbed readily based on the generalizations obtained. However, this does not eliminate the adsorption or binding of these compounds onto the membrane, or direct tissue damage caused by the strong acidity or basicity. Other mechanisms of absorption such as pinocytosis of liquid droplets and phagocytosis of solids are possible, but no quantitative data are available for analysis. Evidence is also presented to show that strong acids or bases can be absorbed as ion pairs with appropriate counter ions.Specific examples of QSAR using the following general equation and its simplified forms are presentedlog A = ‐a · (log P)2 + b · log P + c · log (U/D) + d · log mol wt + e · χ + f.The types of compounds discussed include nonelectrolytes, weak acids and bases, cationic molecules, strong acids, surfactants and some high mol wt substances. Relationships of the absorption via different routes (e.g., gastric, intestinal, percutaneous and corneal) are compared.