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Previous permeant partitioning studies with hairless mouse skin (HMS) in the presence of several chemical skin permeation enhancers have revealed that, when such enhancers induce significant skin permeability coefficient enhancement, it is accompanied by significant enhancement in the equilibrium uptake (partitioning) of the permeant into the intercellular lipid component of the stratum corneum (SC). Particularly, it was found that the 1-alkyl-2-pyrrolidones and the 1-alkyl-2-azacycloheptanones, at aqueous solution concentrations that gave skin permeation enhancement (E) of 10 for corticosterone (CS, the permeant), enhanced the equilibrium uptake of β-estradiol (E2β, a surrogate permeant) from the aqueous phase into the intercellular lipids of HMS SC by a factor of 5–7. This finding raised the question of whether this uptake enhancement induced by the permeation enhancer under equilibrium conditions would be essentially the same as that determined kinetically from time-dependent permeation experiments utilizing appropriate SC membrane models and Fick's laws of diffusion to treat the data. HMS transport experiments were conducted with CS as the permeant and 1-octyl-2-pyrrolidone (OP) and 1-hexyl-2-azacyloheptanone (HAZ) as the enhancers. In treating the experimental data, a one-layer skin transport model (SC only) and a two-layer model (SC layer and the epidermis/dermis layer) were both investigated. Both the partition coefficient enhancement (EK) and the diffusion coefficient enhancement (ED) were deduced from the data treatment. The results showed that when the total transport enhancement of CS was around 11, EK was in the range of 6–8 and ED was in the range of 1.5–1.9 using both the one-layer and the two-layer models. This EK value was found to be in good agreement with the E2β partition enhancement obtained directly under equilibrium conditions in previous studies. This indicates that (a) the rate-limiting domain for the transport of the lipophilic permeants across HMS and the HMS SC intercellular lipid domain probed in the equilibrium partitioning experiments are essentially the same, and (b) the total flux enhancement (E) of lipophilic permeants across HMS was driven mainly by enhancing the partitioning of the permeant into the rate-limiting domain (EK) and secondarily by enhancing the diffusion coefficients (ED) of the permeant in the domain. Comparison of the one-layer and two-layer skin model results revealed that non-steady-state transport of lipophilic compounds across HMS was better described by the two-layer model because the dermis/viable epidermis played a significant role in lipophilic permeant binding.