Chapter 8 - Permeability

Abstract

Permeability also is important in cell-based biological assays in discovery, where the compound must permeate through the cell membrane to reach an intracellular therapeutic target. Prediction of in vitro permeability can enhance a wide range of drug discovery investigations, help with understanding cell-based bioassays, and assist prediction and interpretation of in vivo pharmacokinetics results. Drug molecules encounter several different membrane barriers in living systems. They include gastrointestinal (GI) epithelial cells, blood capillary wall, hepatocyte membrane, glomerulus, restrictive organ barriers, and the target cell membrane. Permeability affects many factors that determine pharmacology in both living systems and in vitro discovery experiments. Two of these factors described in detail are bioavailability and cell-based biological activity assays. The best way to improve permeability is structural modification. Several strategies for improving permeability are examined. These strategies are based on a few fundamental concepts: reduce ionizability, increase lipophilicity, reduce polarity, or reduce hydrogen bond donors or acceptors.