Mechanism of enhanced dermal permeation of 4-cyanophenol and methyl paraben from saturated aqueous solutions containing both solutes.

Dermal permeation through human epidermis and uptake into isolated human stratum corneum (SC) that was and was not delipidized were measured for 2 model compounds, 4-cyanophenol (CP) and methyl paraben (MP), from saturated aqueous solutions containing 1 or both compounds. Because the solutions were in equilibrium with the pure CP and MP, the thermodynamic activity of the compounds was constant. Compared with compounds that are known permeation enhancers, MP and CP would not normally be expected to act as enhancers. Nevertheless, when both compounds were present, the steady-state fluxes through the epidermis increased by factors of 5.2 and 2.6 for MP and CP, respectively. Within the variability of the measurements, this increase in MP flux is consistent with the 6.4-fold increase in the SC uptake, which occurs primarily into the nonlipid regions of the SC. In contrast, the 1.6-fold increase in CP uptake when MP is present is too small to explain the increase in CP flux. These results suggest that CP enhances the skin permeation of MP by primarily increasing the solubility of MP in the SC, especially in the nonlipid regions, while MP increases the skin permeation of CP by enhancing both the solubility and diffusivity of CP in the SC.

Inter- and intralaboratory variation of in vitro diffusion cell measurements: an international multicenter study using quasi-standardized methods and materials.

In vitro measurements of skin absorption are an increasingly important aspect of regulatory studies, product support claims, and formulation screening. However, such measurements are significantly affected by skin variability. The purpose of this study was to determine inter- and intralaboratory variation in diffusion cell measurements caused by factors other than skin. This was attained through the use of an artificial (silicone rubber) rate-limiting membrane and the provision of materials including a standard penetrant, methyl paraben (MP), and a minimally prescriptive protocol to each of the 18 participating laboratories. "Standardized" calculations of MP flux were determined from the data submitted by each laboratory by applying a predefined mathematical model. This was deemed necessary to eliminate any interlaboratory variation caused by different methods of flux calculations. Average fluxes of MP calculated and reported by each laboratory (60 +/- 27 microg cm(-2) h(-1), n = 25, range 27-101) were in agreement with the standardized calculations of MP flux (60 +/- 21 microg cm(-2) h(-1), range 19-120). The coefficient of variation between laboratories was approximately 35% and was manifest as a fourfold difference between the lowest and highest average flux values and a sixfold difference between the lowest and highest individual flux values. Intralaboratory variation was lower, averaging 10% for five individuals using the same equipment within a single laboratory. Further studies should be performed to clarify the exact components responsible for nonskin-related variability in diffusion cell measurements. It is clear that further developments of in vitro methodologies for measuring skin absorption are required.