The effect of dermal clearance on epidermal concentrations of topically applied drugs is poorly understood but fundamental to absorption kinetics and efficacy. Previously generated data quantifying changes in flux and epidermal retention of a series of alcohols and steroids was used to relate solute physicochemical properties to changes in flux under conditions of infinite vasoconstriction (full-thickness skin) and infinite vasodilatation (epidermal membranes) using stepwise regression. Flux through full-thickness skin decreased with increasing lipophilicity, up to 45-fold for alcohols and 4-fold for steroids. This change in flux was not uniformly predictable for the solutes, with alcohols showing a strong dependency on molecular weight (MW), indicative of stratum corneum diffusion limited penetration. Epidermal retention of lipophilic solutes was found to increase up to sixfold in full-thickness skin, with changes predictable from a combination of log P and MW (correlation 0.898, p < 0.001). This study shows that drug epidermal retention and penetration is significantly affected by dermal clearance, however aspects of these effects may be able be predicted from solute physicochemical properties, though extrapolation of the results of this study to other solute-membrane combinations remains to be proven. These findings have significant implications in understanding the effects of erythema and vasoconstriction on topical drug efficacy.