Permeability（药物渗透性）课件.ppt

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1、Permeability,We Are Determined To Serve You Better,Aug.18,2010,Permeability,Introduction to Permeability MechanismModification Strategies to Improve PermeabilityPrediction of Permeability,Permeability Fundamentals,Drug molecules encounter several different membrane barriers in living systems,for exa

2、mple,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),Structure o

3、f some common 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 the net movement

4、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

5、 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 permeabili

6、ty-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

7、 are approximately 8A in size.Efflux Permeability:the active transport of compounds from inside the cell or membrane back into the lumenal space,for example,P-glycoprotein(Pgp)and breast cancer resistance protein(BCRP)well-known efflux transporters.,4,Combined permeability,5,6,Two of these factors:b

8、ioavailability and cell-based biological activity assays.Drug absorption in the GI tract after oral administration depends heavily on permeability.Permeability can limit the activity of compounds in cell-based assays.,Permeability Effects,Permeability Effect on cell-based assays,7,Permeability Struc

9、ture Modification Strategies,Formulations are not effective in fixing permeability.Several strategies for improving permeability:reduce ionizability,increase lipophilicity,reduce polarity,or reduce hydrogen bond donors or acceptors,8,Ionizable Group to non-ionizable Group,9,Add Lipophilicity,10,Isos

10、teric Replacement of Polar Groups,11,Esterify Carboxylic Acid,12,Reduce Hydrogen Bonding and Polarity,13,Reduce Size,14,Add Nonpolar Side Chain,15,Prodrug,16,Permeability Method,In silico methods are available for calculating in vivioand in vitro permeability.,In vitro Permeability Methods,Immobiliz

11、ed artificial membrane(IAM)HPLCCell layerParallel artificial membrane permeability assay(PAMPA),IAM HPLC:The chromatographic capacity factor k increases with Increasing affinity for the phospholipid phase.The correlation to permeability may be better than Log D,lesspredictive than some other methods

12、.Require very little material,imputity not interfere with prediction,In vitro Permeability Methods,Cell layer Method for PermeabilityCaco-2,MDCK and PAMPA,Comparison of CaCo-2 and PAMPA Method,PAMPA correlates only with passive diffusion,whereasCaco-2 provides additional permeability mechanism.,In Depth Permeability Methods,26,Any comments?,Thanks!,