Influences of ethanol on simultaneous diffusion and metabolism of Beta-estradiol in skin

The influences of ethanol upon simultaneous diffusion and metabolism of beta-estradiol (E2beta) in skin have been systematically examined using a quantitative biophysical model approach. Baseline studies (in saline) with hairless mouse skin have been carried out using a two-chamber diffusion cell system. The strategy involved (a) considering a general three-layer skin model (stratum corneum, epidermis, and dermis), (b) considering three possible enzyme distributions (Model A: homogeneous enzyme distribution across both epidermis and dermis, Model B: homogeneous enzyme distribution in the epidermis, and Model C: homogeneous enzyme distribution in the 'basal cell layer' of the epidermis), and (c) carrying out a wide range of independent diffusion experiments so that a 'best' model may be deduced in which all of the experimental data are consistent with the model and a single set of transport and metabolism parameters. Analysis of all of the experimental data has demonstrated that Model C is superior to Model B and Model A. Two important effects of ethanol (at low concentration in aqueous media, < 35%) have been quantified for the 'symmetric' situation (i.e., identical ethanol/saline composition in both chambers). First, ethanol functions as a permeation enhancer for E2/beta and for E1 (metabolite). The second role played by ethanol in Eb2beta transport is an inhibitor of the enzymatic conversion of E2beta to E1. Experiments over a wide range of conditions have shown that, as in the case of the baseline studies (above), Model C also best describes the effects of ethanol on the simultaneous transport and metabolism of E[2beta in hairless mouse skin. A novel theoretical model/method has been developed to predict permeant transport across skin for the 'asymmetric' situation (i.e., ethanol/saline in the donor chamber and saline only in the receiver chamber) where there is significant cotransport of ethanol along with E2/beta. The method has successfully predicted effects of ethanol on the transport of ethanol and on the simultaneous diffusion and metabolism of E2/beta in hairless mouse skin using parameter values deduced from experiments conducted under 'symmetric' conditions. Finally, the experimental and theoretical methods developed with hairless mouse skin have been successfully applied to fresh human skin.