Quantitative structure-toxicity relationships using TOPS-MODE. 3. Structural factors influencing the permeability of...

The permeability of a series of 12 commercial solvents through living human skin were studied by using a topological sub-structural approach (TOPS-MODE). We first analyzed the influence of several physicochemical parameters used in describing the skin permeability of the solvents. No single significant relationship was found between any of these physicochemical properties and the permeability of the solvents. A QSAR model using TOPS-MODE descriptors was obtained and validated. This model accounted for more than 95% of the variance in the experimental permeability of these solvents. Using the derived model, the structural factors responsible for the permeability of this series of solvents through living human skin were identified. Methyl groups bonded to heteroatoms or to CH2 groups resulted in the greatest contributions to skin permeability and these groups were considered to be "permeability enhancers". In contrast, groups of the type X = O (X = S, C) were found to be "permeability inhibitors" because they possessed negative contributions to the logarithm of permeability in all of the studied solvents. Drawing on the idea of permeability "enhancers" and "inhibitors", we hypothesized that the solvents needed to orientate themselves in front of the stratum corneum layer first before penetrating through the skin.