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, l eucine, phenylalanine, and cyclohexylalanine with amino acids in the D-conf iguration were prepared. Partition coefficients for the peptidemimetics wer e obtained in the octanol/water (log P-octanol/water), hydrocarbon/octanol (Delta log P), and heptane/ethylene glycol (log P-heptane/glycol) systems i n order to explore the contributions of solute volume, or surface area, and hydrogen-bond potential to the permeability of the solutes. Permeability c oefficients were obtained in Caco-2 cell monolayers as a model of the human intestinal mucosa. The results were interpreted in terms of a partition/di ffusion model for solute transport where membrane partitioning into the per meability-limiting membrane microdomain is estimated from the solvent parti tion coefficients. Neither log P-octanol/water nor Delta log P alone correl ated with cellular permeability for all the solutes. In contrast, log P-hep tane/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/gly col contains contributions from all these solute properties. The results de monstrate that both hydrogen-bond potential and volume of the solutes contr ibute to permeability and suggests that the nature of the permeability-limi ting microenvironment within the cell depends on the properties of a specif ic solute. Collectively, these findings support the conclusion that a gener al model of permeability will require consideration of a number of differen t solute structural properties.