Physicochemical properties in pharmacokinetic lead optimization

Abstract

The ADME ( absorption, distribution in the body, metabolism and elimination from the body) profile of a drug determines its pharmacokinetics in the body. Modern drug design includes the modeling of pharmacokinetically favorable behavior. The pharmacokinetic parameters of most interest concern intestinal absorption, blood–brain barrier (BBB) passage and metabolism. Traditionally, experimental parameters such as partition coefficients and chromatographic capacity factors have been used for the estimation of intestinal absorption or BBB passage of newly synthesized compounds. Several studies have shown a sigmoidal relationship between intestinal absorption and lipophilicity. The latter is usually expressed by the apparent partition coefficient log D in a biphasic system at physiological pH or by the affinity to a lipophilic phase determined by chromatographic techniques. In contrast, structure-based descriptors need no experimental investigation of the compound studied. The most relevant descriptors give information on hydrogen-bonding characteristics and molecular volume. In recent years, attempts have been made to recognize substrates for multidrug resistance proteins by their structure characteristics without crucial success. There is evidence that multidrug resistance is not only driven by direct protein–substrate recognition, but also by the behavior of the compound in the lipid environment of the protein.