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

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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 Poctanol/water), hydrocarbon/octanol (Δ log P), and heptane/ethylene glycol (log Pheptane/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 Poctanol/water nor Δ log P alone correlated with cellular permeability for all the solutes. In contrast, log Pheptane/glycol gave a qualitatively better correlation. With regard to solute properties, log Poctanol/water is predominantly a measure of solute volume, or surface area, and hydrogen-bond acceptor potential, while Δ log P is principally a measure of hydrogen-bond donor strength. Log Pheptane/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.