Human skin permeation and partition: general linear free-energy relationship analyses

Abstract

Literature values of the permeability coefficient for permeation of human skin from water have been adjusted for ionization in water and adjusted for temperature. The obtained values of log K(p) for 119 solutes at 37 degrees C have been correlated with Abraham descriptors to yield an equation with R(2) = 0.832 and SD = 0.46 log units. Three separate test sets of 60 compounds had log K(p) predicted with an SD of 0.48 log units. The main factors that influence log K(p) are solute hydrogen bond basicity that lowers the permeability coefficient and solute volume that increases the permeability coefficient. Human skin-water partition coefficients, as log K(sc), have been collected for 45 compounds and yield an equation with R(2) = 0.926 and SD = 0.22 log units. We have compared the log K(p) equation to equations for various other processes, but have found no process that appears to be similar to that for skin permeation. The nearest process to skin-water partition is the isobutanol-water partition system. An equation for lateral diffusion in the stratum corneum is shown to be reasonably close to various diffusion-related processes.