Permeation of Mouse Skin and Silicone Rubber Membranes by Phenols: Relationship to In Vitro Partitioning

Abstract

A discrepancy has been noted in the relationship between the relative skin permeabilities of phenols and their lipophilicities as expressed in commonly used octanol:water partition coefficients (PCoctanol:water). The lack of correlation between partitioning and permeability is seen with the nitrophenols, particularly 4-nitrophenol. In the present study, the permeability coefficients of 4-nitrophenol and several other phenols through skin and a model lipophilic membrane made of silicone rubber were found to be independent of concentration, ruling out concentration-dependent molecular aggregation as the cause of the partitioning-permeability incongruity. An unexpectedly low permeation rate was observed for the diffusion of 4-nitrophenol through the synthetic, silicone rubber membrane, confirming the anomalous position of this phenol in permeability relative to the octanol:water partitioning scale. However, when oil:water (o/w) partition coefficients for the phenolic compounds based on either n-hexane, CH2Cl2, CHCl3, or silicone rubber as the water immiscible phase are used, permeability coefficients for the skin and the synthetic membrane followed expected permeation-partitioning dependencies. On this basis, it appears that PCoctanol:water does not properly reflect the lipophilicity of the phenols with respect to partitioning into skin and silicone rubber during mass transfer.