The effects of ethanol on the transport of lipophilic and polar permeants across hairless mouse skin: Methods/validation of a novel approach

Abstract

The influence of ethanol on the in vitro transport behavior of some lipophilic and polar/ionic permeants in hairless mouse skin has been investigated over a 0–100% ethanol/saline concentration range in a two-chamber diffusion cell. The lipophilic permeants were employed in probing the transport enhancing effects of ethanol upon the lipoidal pathway of the stratum corneum, and the polar/ionic permeants were used to quantify the influence of ethanol on thepore pathway of the stratum corneum over the entire range of ethanol concentrations. The following were the important interpretations of the data. The lipophilic permeants (estrone, ß-estradiol, and hydrocortisone) were mainly transported via the lipoidal pathway up to around 50% ethanol. The permeation enhancement factor, E, for the lipoidal pathway was calcuklated from the transport data for the three lipophilic permeants. In order to calculate the E values, it was first necessary to establish the validity of Henry's law by comparing the ratios of permeant solubilities (in different ethanol/saline solutions) to ratios of permeant partition coefficients (in hexadecane/ethanol-saline systems). The calculated E values were found to be about the same for all three permeants: E = 7.0 ± 2.0 at 25% ethanol and E = 112 ± 19 at 50% ethanol. These large enhancing effects of ethanol upon the lipoidal pathway were somewhat surprising, and it is suggested that ethanol (< 50%) may work as an effective ‘fluidizing’ agent at some locus in the stratum corneum lipid bilayer at or near the polar head plane, but not in the bilayer hydrocarbon interiors. The polar/ionic permeants (tetraethylammonium bromide, mannitol, estrone ammonium sulfate, and vidarabine) all were transported via the pore pathway at all ethanol concentrations. Ethanol up to around 25% had little effect upon the pore pathway; however, at higher concentrations (∼ 50%), ethanol greatly enhanced pore transport and, at very high ethanol levels (t̆~ 75%), the pore pathway appeared to dominate the transport of all permeants including the lipophilic permeants.