Does slowly reversible binding to keratin contribute to stratum corneum reservoir function?

The existence of a storage capacity or reservoir function within human stratum corneum (HSC) for topically applied chemicals is well documented. However, the source of this reservoir remains ambiguous and may well depend on the chemical and the exposure conditions. We have investigated the role of reversible binding to keratin in contributing to this phenomenon by measuring the kinetics of uptake and desorption of solutes from isolated HSC, delipidized HSC, and silicone membrane from buffered aqueous solutions (pH 5.5) in vitro. A lipophilic permeant, geraniol, was studied for periods ranging from 24 to 168 h. Additional desorption data for testosterone and 1-propanol from isolated HSC were drawn from the literature. Results were compared with theoretical predictions for a homogeneous membrane with either no binding, equilibrium binding or slowly reversible binding. The theory includes a hitherto unpublished analysis of the short-time and long-time behavior of such systems. Calculations were also conducted for selected corticosteroids, the original stimuli for the HSC reservoir function concept. The HSC and delipidized HSC data for geraniol were most consistent with slowly reversible binding in the protein phase of the tissue. Almost complete desorption was achieved within 2-3 h of exposure to permeant-free buffer. Testosterone and 1-propanol data were consistent with this picture. Model-based calculations for corticosteroids, however, predict much longer retention times in the stratum corneum - up to two weeks - when extrapolated to the case of partially hydrated skin. We conclude that, while slowly reversible binding of many lipophilic permeants in the protein phase of the tissue is supported, the combination of very low diffusion rates in the lipid phase with strong equilibrium binding in the protein phase is a major contributor to HSC reservoir function for corticosteroids.