Permeability of frog skin to chemicals: effect of penetration enhancers

Rarely do commercial chemical products contain solely the active chemical/ingredient. It is therefore important to consider whether ingredients other than the active may: 1) alter absorption of the active chemical, or 2) be absorbed themselves, resulting in systemic effects. Frogs have highly permeable skin and are routinely exposed to commercial chemical products in the environment or therapeutically. Ethanol and propylene glycol (PG), which have known penetration-enhancing effects, are commonly included in such products. The current study has therefore investigated the in vitro absorption kinetics through Rh. marina skin of three model chemicals – caffeine, benzoic acid, and ibuprofen – formulated individually as solutions containing: 1%, 10% or 30% v/v ethanol, or 20% v/v PG. Differential scanning calorimetry and histology were used to characterise fresh frog skin, investigate the mechanism of these enhancers in frog skin, and to determine whether these enhancers significantly affected skin structure. Results showed that the extent of absorption enhancement was influenced by chemical, enhancer and skin region, and that enhancement was generally not consistent for individual enhancers or skin regions. The exception was 1% v/v ethanol, which did not significantly alter flux across the skin for any of the chemicals evaluated. Caffeine absorption was not enhanced by any of the investigated penetration enhancers, and was in fact significantly reduced by 30% v/v ethanol and PG. Ethanol caused concentration-dependant changes in skin morphology and should be avoided in concentrations ≥10% v/v. PG, however, caused minimal changes to the skin and consistently improved absorption of benzoic acid and ibuprofen through all skin regions. Owing to the significant changes in skin structure following ≥10% v/v ethanol exposure, it is recommended to avoid its use in frogs. For enhancement of penetration of moderately-to-highly lipophilic chemicals, this study has identified 20% v/v PG should to be the enhancer of choice.