Chapter 5 - Lipophilicity

Abstract

Lipophilicity is a property that has a major effect on absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) properties as well as pharmacological activity. Lipophilicity has been studied and applied as an important drug property for decades. It can be quickly measured or calculated and is correlated to many other properties, such as solubility, permeability, metabolism, toxicity, protein binding, and distribution. The traditional approach for assessing lipophilicity is to partition the compound between immiscible nonpolar and polar liquid phases. Lipophilicity is an underlying structural property that affects higher-level physicochemical and biochemical properties. It changes with the conditions of the phases, including the following: partitioning solvents/phases, pH, ionic strength, buffer, and co-solutes or co-solvents. It can be correlated to various models of drug properties affecting ADME/Tox. They include permeability, absorption, distribution, plasma protein binding, metabolism, elimination, and toxicity. It often is an effective guide for modifying the structure of a lead series to improve a property. The effects of lipophilicity on specific properties and structure modification strategies are discussed.