Physicochemical determinants of passive membrane permeability: role of solute hydrogen-bonding potential and volume.

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 ...