title: 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.
authors.affiliation: Drug Absorption and Transport, Pharmaceutical Development, Pharmacia, Kalamazoo, MI 49007, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Goodwin
authors.forename: R A
authors.initials: RA
authors.lastname: Conradi
authors.forename: N F
authors.initials: NF
authors.lastname: Ho
authors.forename: P S
authors.initials: PS
authors.lastname: Burton
mesh_terms: D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D006801:Humans; D006860:Hydrogen Bonding; D008954:Models, Biological; D018716:Molecular Mimicry; D000442:Octanols; D010649:Phenylalanine / Q000737:chemistry*; D012995:Solubility; D014867:Water
chemical_list: D000442:Octanols; D014867:Water; D010649:Phenylalanine