Permeability(药物渗透性).ppt

Permeability Permeability Fundamentals Structure of some common phospholipids Permeability Mechanism Case of Passive diffusion permeability Other routes of permeability Combined permeability Permeability Effect on cell-based assays Permeability Structure Modification Strategies Ionizable Group to non-ionizable Group Add Lipophilicity Isosteric Replacement of Polar Groups Esterify Carboxylic Acid Reduce Hydrogen Bonding and Polarity Reduce Size Add Nonpolar Side Chain Prodrug Permeability Method In vitro Permeability Methods In vitro Permeability Methods Comparison of CaCo-2 and PAMPA Method In Depth Permeability Methods External Basic Research * External Basic Research * Permeability We Are Determined To Serve You Better? Aug. 18, 2010 Introduction to Permeability Mechanism Modification Strategies to Improve Permeability Prediction of Permeability 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; Other components: cholesterol, transmembrane proteins (channels, transporters, receptors) 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 the net 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