Permeability - SKKU

Permeability 2013.11.08 Contents Permeability Overview Permeability Fundamentals Permeability Effect Permeability Structure Modification Strategies Problem

Peameability Overview Permeability is the velocity of molecule passage through a membr ane barrier. Permeability is a determinant of intestinal absorption and oral bioa vailability.

Optimizing passive diffusion is productive because it is the predo minant mechanism for absorption of most commercial drugs. Permeability is increased by removing ionizable groups, increasing Log P, and decreasing size and polarity. Permeability Fundamental s

Different membranes can have different permeabilities for a comp ound. Passive Diffusion Luminal Cytoplas m Abluminal lipid bilayer

Membrane Passive diffusion is driven by a concentration gradient (High->Low Concentration) It has been estimated that 95% of commercial drugs are predominantly absor bed in the GI tract by passive diffusion

It is important to remember that permeability is much higher for more liphop hilic molecules than for polar molecule pH and pKa play important roles in passive diffusions. Passive Diffusion

Passive Diffusion The passive diffusion of acids is much higher at low pH. The passive diffusion of bases is low at low pH. Passive Diffusion

For an acid passive diffusion is enhanced in the direction of the higher pH because of the ionization equilibrium. On the other hand, base passive diffusion is enhanced in the direction o f the lower pH. Endocytosis

Compounds may be engulfed by the membrane, pass through th e cell within the vesicle, and be released on the other side. Minor interest for small molecule drug discovery. Active uptake Compound binds to a transmembrane protein and moves

through the membrane. Active transport requires the expenditure of energy, commonly two ATPs for each molecule transported. Palacellular GI tract or other organs are sometimes termed leaky because of the somewhat loose junctions between the cells that allow molecules to

slip between. Paracellular permeability in the GI tract is available primarily to com pounds that have a molecular weight less than 180 Da and are polar. Efflux Efflux, the active transport of compounds from inside the cell or membrane back into the lumenal space.

Pgp(p-glycoprotein) BCRP (breast cancer resistance protein) Combined Permeability

GI track Passive diffusion Absorption BBB Active transport, efflux Factors that affect permea bility Concentration gradient

pH polarity Expression of transporter Transporter Km

Affinity of the compound for various transporters The size of the pores between membrane barrier Permeability Effect Living System Bioavailabilit y

In vitro discovery Cell based Activity assay Bioavailability Compounds with low permeability typically have low bioavailabilit y

In this case, passive diffusion is limited for the highly charged acid ic compound (pKa= 4.5). Cell based Activity assay Both Good enzyme activity and permeability were required i n order to produce good bioactivity in the cell based assay.

Cell based Activity assay Modification Strategies 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 Modification Strategies Ionizable group to non-ionizable group Modification Strategies Add lipophilicity

Modification Strategies Isosteric replacement of polar groups Modification Strategies Esterify carboxylic acid Modification Strategies

Reduce hydrogen bonding and polarity Modification Strategies Reduce size Modification Strategies Add nonpolar side chain

Modification Strategies Prodrug Problem 1. What is the predominant permeability mechanism for absorption of most comm ercial drugs?

2. What are the structural properties of compounds that undergo paracellular per meation? 3. How will passive diffusion permeability change as pH increases from 4.5 to 8 fo r: (a) basic compound, (b) acidic compound?

4. List important permeability barriers for drug discovery. 5. Which of the following structural modifications likely will improve permeability?: (a) change an amine to a methyl, (b) add a hydroxyl group, (c) remove a propyl group, (d) change a carboxylic acid to an ethyl ester, (e) change a carboxylic acid to a tetrazole.

6. For the following lead compared, what structural modifications could you make that might improve permeability? Problem 7. Permeability is important for which of the following?: (a) absorption in intestine, (b) CYP metabolism, (c) BBB penetration, (d) dissolution in the intestinal lumen, (e) in vitro cell-based assay, (f) to reach intracellular targets in vivo.

8. Following are groups that could be added to a lead compound that is MW 300 and has ClogP 2.0. Rank them from lowest to highest predicted permeability of the produ ct: (a) CH3, (b) OH, (c) OCH3, (d) COOH. 9. Following are groups that could be added to a lead compound that is MW 450 and has ClogP 4.5. Rank them from lowest to highest predicted permeability of the produ ct: (a) C6H5, (b) CH3, (c) C3H7.

10. Following are groups that could be added to a lead compound that is MW 250 and has ClogP 0.0. Rank them from lowest to highest permeability of the product: (a) CH 3, (b) C6H11, (c) C3H7 Contents Permeability Method Overview In Silico Permeability Method In Vitro Permeability Method In Depth Peameability Method

Permeability Method Overview In silico methods are available for calculating in vivo and in vitro p ermeability, such as intestinal absorption, Caco-2, and parallel arti ficial membrane permeability assay (PAMPA). High-throughput permeability methods utilize high-performance li quid chromatography (immobilized artificial membrane), artificial membranes (PAMPA), and cell layers(Caco-2).

In-depth study of permeability uses portal vein cannulation and in situ perfusion. In Silico Permeability Method In Vitro Permeability Meth od

IAM HPLC Test compounds partition between the aqueous mobile phase and the phospholipid phase. Compounds are rank ordered by k, which indicates a higher lipop hilicity or phospholipids affinity. The parameters of this affinity cor relate with permeation.

In Vitro Permeability Meth od Cell layer Permeability assay Caco-2 In Vitro Permeability Meth od

In Vitro Permeability Meth od Artificial Membrane Permeability assay PAMPA reduces the cost and increases the throughput of permeability assays. Instead of a barrier made of living cells, the PAMPA barrier is made of phospholipids solubilized in along-chain hydrocarbon. In Vitro Permeability Meth

od Comparisn of Caco-2 and PAMPA Method Comparison of Caco-2 and PAMPA permeability values from the same compound can provide insight on permeability mechanisms.

In Depth Permeability Met hods

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