文档介绍：Permeability We Are Determined To Serve You Better ? Aug. 1 8, 2010 Permeability ? Introduction to Permeability Mechanism ? Modification Strategies to Improve Permeability ? Prediction of Permeability Permeability Fundamentals Permeability Fundamentals Drug molecules encounter several different membrane barriers in living systems, for example, GI epithelial cells, blood capillary wall, hepatocyte membrane, glomerulus , organ barriers, the target cell membrane. Components: ? Hydrophilic polar head group; ? Hydrophobic fatty acid chain of phospholipids; ? ponents: cholesterol, transmembrane prot eins (channels, transporters, receptors) Structure of mon phospholipids Permeability Mechanism Five major permeability mechanism: ? Passive diffusion ? Active uptake ? Endocytosis ? Efflux ? Paracellular 2 Passive diffusion permeability ? The most important permeability mechanism for drug discovery ? Driven by a concentration gradient, with movement of molecules from the area of higher concentration to the area of lower concentration. ? Permeability is much higher for more lipophilic molecules than for polar molecules. Neutral molecules are much more permeable than their charged forms. ? pH and pKa play important roles in passive diffusion. The passive diffusion of acids is much higher at low pH, whereas the passive diffusion of bases is low at low pH. The passive diffusion permeability of neutral molecules is unaffected by pH. Case of Passive diffusion permeability 3 Other routes of permeability ? Endocytosis Permeability: another route of permeability-only minor interest for small molecule. ? Active uptake permeability: bound to a transmembrane protein and moves through the membrane. It often occurs against the concentration gradient. ? Paracellular Permeability: small and polar molecules pass between the epithelial cells through “ pores ” or channels that are approximately 8A in size. ? Efflux Permeability: the active transport pounds fr