Lipophilicity & Permeability 김연수

Chapter 5. Lipophilicity

5.1 Lipophilicity Fundamentals Partition into a non-polar lipid matrix versus an aqueous matrix Non-polar phase – octanol Aqueous phase – buffer,

5.1 Lipophilicity Fundamentals - log of the partition coefficient at a pH where all of the compound molecules are in the neutral form

5.1 Lipophilicity Fundamentals - log of the distribution coefficient at a specified pH(x) where the compound molecules may be in the ionic form and neutral form Ionization depends on the pH, the pKa

5.1 Lipophilicity Fundamentals Molecular volume (molecular weight) - size of the cavity Dipolarity - Polar alignment of the molecule Hydrogen bond acidity (Hydrogen bond donation) - Hydrogen bonding with the solvent Hydrogen bond basicity (Hydrogen bond acceptance) - Hydrogen bonding with the solvent

5.1 Lipophilicity Fundamentals Different interactions of the solvent and solute molecules Partitioning solvents/phases Degree of ionization pH Polarity of the aqueous phase Ionic strength Polarity, Molecular interactions, Formation of in situ salts Buffer Interact with solutes and change their partitioning behavior Co-solutes or co-solvents

5.2 Lipophilicity Effects A general guide for optimal absorption is to have a moderate Log P(range 0-3) Good balance of permeability and solubility More non-polar and have poor aqueous solubility More polar and have poorer lipid bilayer permeability

5.2 Lipophilicity Effects

Problems 4. Why is a low Log P unfavorable for absorption? Why is high Log P unfavorable for absorption? Low Log P : low passive diffusion permeability High Log P : low solubility 6. At a Log D 7.4 of 2, which of the following can be predicted? : (a) high intestinal absorption (b) low solubility (c) high permeability (d) high metabolism (e) high central nervous system penetration

Chapter 8. Permeability

8.1 Permeability Fundamentals

8.1.1 Passive Diffusion Permeability - The most important permeability mechanism - Concentration gradient - pH and pKa play important roles in passive diffusion

8.1 Permeability Fundamentals Endocytosis Permeability - Compound may be engulfed by membrane, pass through the cell within the vesicle

8.1 Permeability Fundamentals Active Uptake Permeability - Molecules may be permeable by active uptake transport - Against the concentration gradient

8.1 Permeability Fundamentals Paracellular Permeability - If molecules are small and polar, they might pass between cells through pores or channels

8.1 Permeability Fundamentals Efflux Permeability

8.2 Permeability Effects Effect of Permeability on Bioavailability - Compounds with low permeability typically have low bioavailability

8.2 Permeability Effects Effect of Permeability on Cell-Based Activity Assays - Good Cell-based activity requires both good enzyme activity and permeability

8.2 Permeability Effects Effect of Permeability on Cell-Based Activity Assays

8.3 Permeability Structure Modification Strategies

8.3.1 Ionizable Group to Non-ionizable Group Less polar and non-ionizable In vitro permeability is higher, In vivo oral bioavailability is higher

8.3 Permeability Structure Modification Strategies Add Lipophilicity More lipophilic In vitro permeability is higher, In vivo oral bioavailability is higher

8.3 Permeability Structure Modification Strategies Isosteric Replacement of Polar Groups

8.3 Permeability Structure Modification Strategies Esterify Carboxylic Acid

8.3 Permeability Structure Modification Strategies Reduce Hydrogen Bonding and Polarity

8.3 Permeability Structure Modification Strategies Reduce Hydrogen Bonding and Polarity

8.3 Permeability Structure Modification Strategies Reduce Hydrogen Bonding and Polarity

8.3 Permeability Structure Modification Strategies Reduce Size

8.3 Permeability Structure Modification Strategies Reduce Size

8.3 Permeability Structure Modification Strategies Add Nonpolar Side Chain

8.3 Permeability Structure Modification Strategies Prodrug

Problems 1.What is the predominant permeability for absorption of most commercial drugs? passive diffusion 5. Which of the following structural modifications likely will improve permeability? : (a) change an amine a methyl (b) add a hydroxyl groups (c) remove a propyl group (d) change a carboxylic acid to an ethyl ester (e) change a carboxylic acid to a tetrazole