lipophilicity & permeability 2015.10.14 김연수. chapter 5. lipophilicity
TRANSCRIPT
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 speci-fied 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 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
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
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
8.1.2 Endocytosis Permeability - Compound may be engulfed by membrane , pass
through the cell within the vesicle
8.1 Permeability Fundamentals
8.1.3 Active Uptake Permeability - Molecules may be permeable by active uptake
transport - Against the concentration gradient
8.1 Permeability Fundamentals
8.1.4 Paracellular Permeability - If molecules are small and polar , they might pass
between cells through pores or channels
8.2 Permeability Effects
8.2.1 Effect of Permeability on Bioavail-ability
- Compounds with low permeability typically have low bioavailability
8.2 Permeability Effects
8.2.2 Effect of Permeability on Cell-Based Activity Assays
- Good Cell-based activity requires both good en-zyme activity and permeability
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 Permeability Structure Modifi-cation Strategies
8.3.2 Add Lipophilicity
More lipophilic
In vitro permeability is higher , In vivo oral bioavailability is
higher
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