Skin penetration and metabolism of topical glucocorticoids in reconstructed epidermis and in excised human skin

Purpose. To investigate pharmacokinetic differences between the nonhalogena ted double ester prednicarbate (PC) and the fluorinated monoester betametha sone 17-valerate (BM17V) their metabolism in human keratinocytes and fibrob lasts as well as their permeation and biotransformation in reconstructed ep idermis and excised human skin was compared. Special attention was given to the 17-monoesters because of their high receptor affinity and antiprolifer ative effects. Methods. Glucocorticoid penetration was determined using Franz diffusion ce lls, quantifying metabolite concentrations by HPLC. Chemical stability and reactivity of the monoesters was determined by molecular modeling analysis. Results. PC accumulated in the stratum corneum. A considerable amount of pe netrating PC was hydrolyzed by viable keratinocytes to prednisolone 17-ethy lcarbonate (P17EC). P17EC permeated the skin very rapidly when compared to BM17V. Overall P17EC concentrations in viable tissue were low. Inside of th e acceptor fluid, but not within the tissue, P17EC was converted to the mor e stable prednisolone 21-ethylcarbonate (P21EC). Conclusions. The inactivation of highly potent, but also cell toxic, 17-mon oesters to almost inactive 21-congeners seen with isolated cell monolayers appears less important in the skin. In vitro determination of the dermal 17 -monoesters concentrations may allow the prediction of the atrophogenic ris k in man. BM17V levels exceeding P17EC concentrations about 6-fold may cont ribute to its lower tolerance when compared to PC.