Physicochemical Determinants of Passive Membrane Permeability: Role of Solute Hydrogen-Bonding Potential and Volume

Abstract

The relationship of solute structure with cellular permeability was probed. Two series of dipeptide mimetics consisting of glycine, alanine, valine, leucine, phenylalanine, and cyclohexylalanine with amino acids in the D-configuration were prepared. Partition coefficients for the peptidemimetics were obtained in the octanol/water (log P(octanol/water)), hydrocarbon/octanol (Delta log P), and heptane/ethylene glycol (log P(heptane/glycol)) systems in order to explore the contributions of solute volume, or surface area, and hydrogen-bond potential to the permeability of the solutes. Permeability coefficients were obtained in Caco-2 cell monolayers as a model of the human intestinal mucosa. The results were interpreted in terms of a partition/diffusion model for solute transport where membrane partitioning into the permeability-limiting membrane microdomain is estimated from the solvent partition coefficients. Neither log P(octanol/water) nor Delta log P alone correlated with cellular permeability for all the solutes. In contrast, log P(heptane/glycol) gave a qualitatively better correlation. With regard to solute properties, log P(octanol/water) is predominantly a measure of solute volume, or surface area, and hydrogen-bond acceptor potential, while Delta log P is principally a measure of hydrogen-bond donor strength. Log P(heptane/glycol) contains contributions from all these solute properties. The results demonstrate that both hydrogen-bond potential and volume of the solutes contribute to permeability and suggests that the nature of the permeability-limiting microenvironment within the cell depends on the properties of a specific solute. Collectively, these findings support the conclusion that a general model of permeability will require consideration of a number of different solute structural properties.