A thermodynamic and kinetic analysis of human epidermal penetration of phenolic compounds: II. Maximum flux and solute diffusion through stratum corneum lipids

Abstract

Warming the skin is a key means of promoting solute permeation through the skin. Changes in solute permeation associated with variations in skin temperature also assist in understanding the mechanism by which solutes permeate the skin. However, few studies have considered the relative impact of temperature on the main determinants of the maximum flux for a solute across the skin, the solubility of a solute and its diffusivity in the stratum corneum. In this study, we quantified for the first time the thermodynamics associated with the maximum skin fluxes for a series of phenolic compounds of similar size but with varying lipophilicity (defined by the logarithms of their octanol/water partition coefficient, logP). These studies were undertaken using aqueous donor solutions (along with testosterone as a reference solute) across human epidermal membranes in vertical Franz diffusion cells at 4 °C, 24 °C and 37 °C with intermittent receptor sampling and volume replacement over 24 h. Kinetic and thermodynamic analyses included the estimation of the stratum corneum (SC) apparent SC diffusivity from the SC maximum fluxes and SC solubilities and the associated activation energies, enthalpies and entropies for diffusion. The key findings were that the differences in the maximum flux of phenolic compounds varying in lipophilicity mainly arose from differences in SC solubility at the various temperatures and that, at the highest temperature, SC permeability and SC diffusion were affected by SC lipid fluidisation and that variations in SC - water partitioning enthalpies explain some of the previously low activation energies for permeation of the more lipophilic phenols. Higher enthalpies for diffusion were seen for solutes with addition hydrogen bonding capacity and the highest negative entropy was observed with the more compact solutes. Various relationships between the derived thermodynamic parameters were explored and interpreted in a proposed model for solute partitioning into and permeation through the SC intercellular lipid lamellae.