Permeability(药物渗透性).
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Combined permeability
5
Permeability Effects
Two of these factors : bioavailability 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.
6
Permeability Effect on cell-based assays
7
Permeability Structure 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
Permeability
Aug. 18, 2010
We Are Determined To Serve You Better®
Permeability
Introduction to Permeability Mechanism Modification Strategies to Improve Permeability Prediction of Permeability
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 neutral molecules is unaffected by pH.
In Depth Permeability Methods
Thanks!
26
13
Reduce Size
14
Add Nonpolar Side Chain
15
Prodrug
16
Permeability Method
In silico methods are available for calculating in vivio and in vitro permeability.
In vitro Permeability Methods
Immobilized artificial membrane (IAM) HPLC Cell layer Parallel 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, less predictive than some other methods. Require very little material, imputity not interfere with prediction
In vitro Permeability Methods
Cell layer Method for Permeability Caco-2, MDCK and PAMPA
Comparison of CaCo-2 and PAMPA Method
PAMPA correlates only with passive diffusion, whereas Caco-2 provides additional permeability mechanism.
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Case of Passive diffusion permeability
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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 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.
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.
8
Ionizable Group to non-ionizable Group
9
Add Lipophilicity
10
Isosteric Replacement of Polar Groups
11
Esterify Carboxylic Acid
12
Reduce Hydrogen Bonding and Polarity
Components: Hydrophilic polar head group; Hydrophobic fatty acid chain of phospholipids; Other components: cholesterol, transmembrane proteins (channels,
transporters, receptors)
Structure of some common phospholipids
Permeability Mechanism
Five major permeability mechanism: Passive diffux Paracellular
Combined permeability
5
Permeability Effects
Two of these factors : bioavailability 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.
6
Permeability Effect on cell-based assays
7
Permeability Structure 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
Permeability
Aug. 18, 2010
We Are Determined To Serve You Better®
Permeability
Introduction to Permeability Mechanism Modification Strategies to Improve Permeability Prediction of Permeability
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 neutral molecules is unaffected by pH.
In Depth Permeability Methods
Thanks!
26
13
Reduce Size
14
Add Nonpolar Side Chain
15
Prodrug
16
Permeability Method
In silico methods are available for calculating in vivio and in vitro permeability.
In vitro Permeability Methods
Immobilized artificial membrane (IAM) HPLC Cell layer Parallel 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, less predictive than some other methods. Require very little material, imputity not interfere with prediction
In vitro Permeability Methods
Cell layer Method for Permeability Caco-2, MDCK and PAMPA
Comparison of CaCo-2 and PAMPA Method
PAMPA correlates only with passive diffusion, whereas Caco-2 provides additional permeability mechanism.
2
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 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.
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.
8
Ionizable Group to non-ionizable Group
9
Add Lipophilicity
10
Isosteric Replacement of Polar Groups
11
Esterify Carboxylic Acid
12
Reduce Hydrogen Bonding and Polarity
Components: Hydrophilic polar head group; Hydrophobic fatty acid chain of phospholipids; Other components: cholesterol, transmembrane proteins (channels,
transporters, receptors)
Structure of some common phospholipids
Permeability Mechanism
Five major permeability mechanism: Passive diffux Paracellular