Lipophilicity & Permeability 2015.10.14 김연수. Chapter 5. Lipophilicity

Lipophilicity & Permeabil-ity

2015.10.14 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

• ,


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


• - log of the distribution coefficient at a speci-fied pH(x) where the compound molecules may be in the ionic form and neutral form

Ionization depends on the pH , the pKa


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 Partitioning solvents/phases

• Different interactions of the solvent and solute molecules

pH

• Degree of ionization

Ionic strength

• Polarity of the aqueous phase

Buffer

• Polarity , Molecular interactions , Formation of in situ salts

Co-solutes or co-solvents

• Interact with solutes and change their partitioning behavior

5.2 Lipophilicity Effects

• A general guide for optimal absorption is to have a moderate Log P(range 0-3)

Good balance of perme-ability and solubility

More non-polar and have poor aqueous

solubility

More polar and have poorer lipid bilayer per-

meability

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 D7.4 of 2 , which of the following can be predicted? : (a) high intestinal absorption (b) low solubility (c) high permeability (d) high metabo-lism

(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


8.1.2 Endocytosis Permeability - Compound may be engulfed by membrane , pass

through the cell within the vesicle


8.1.3 Active Uptake Permeability - Molecules may be permeable by active uptake

transport - Against the concentration gradient


8.1.4 Paracellular Permeability - If molecules are small and polar , they might pass

between cells through pores or channels


8.1.5 Efflux Permeability

8.2 Permeability Effects

8.2.1 Effect of Permeability on Bioavail-ability

- Compounds with low permeability typically have low bioavailability


8.2.2 Effect of Permeability on Cell-Based Activity Assays

- Good Cell-based activity requires both good en-zyme activity and permeability


8.2.2 Effect of Permeability on Cell-Based Activity Assays

8.3 Permeability Structure Modifi-cation 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


8.3.2 Add Lipophilicity

More lipophilic

In vitro permeability is higher , In vivo oral bioavailability is

higher


8.3.3 Isosteric Replacement of Polar Groups


8.3.4 Esterify Carboxylic Acid


8.3.5 Reduce Hydrogen Bonding and Polarity






8.3.6 Reduce Size


8.3.6 Reduce Size


8.3.7 Add Nonpolar Side Chain


8.3.8 Prodrug

Problems

1. What is the predominant permeability for ab-sorption of most commercial drugs?

passive diffusion5. 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

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Lipophilicity & Permeability 2015.10.14 김연수. Chapter 5. Lipophilicity