Permeability through DOPC/dodecane membranes: measurement and LFER modelling

Area of Science:

• Biophysical Chemistry
• Membrane Science
• Pharmacokinetics

Background:

• Understanding passive membrane permeability is crucial for drug delivery and biomaterial design.
• Ionizable compounds' transport across lipid bilayers is influenced by membrane composition and pH.
• Previous models often simplify the complex interplay of factors affecting permeability.

Purpose of the Study:

• To quantify the intrinsic permeability of ionizable compounds across dioleylphosphatidylcholine (DOPC) membranes.
• To develop a predictive model for membrane permeability using linear free energy relationships.
• To identify the dominant molecular factors governing passive permeation.

Main Methods:

• Measured permeation of 43 ionizable compounds through 2% DOPC in dodecane membranes across a pH range of 3-10.
• Corrected observed permeability for ionization and unstirred water layer diffusion effects.
• Applied Abraham's linear free energy relation (LFER) method for modeling.

Main Results:

• Intrinsic permeabilities were accurately modeled using Abraham's LFER.
• Hydrogen bonding was identified as the primary factor inhibiting permeation.
• Molecular size was found to enhance permeation, while polarity/polarizability effects were less significant.

Conclusions:

• Abraham's LFER provides a robust predictive model for membrane permeability with DOPC membranes.
• Hydrogen bonding is the most critical determinant of passive permeation inhibition.
• The study elucidates the key physicochemical drivers of passive transport across lipid membranes.