Permeability of frog skin to chemicals: effect of penetration enhancers

Abstract

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 chemicalscaffeine, benzoic acid, and ibuprofenformulated 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.

The effect of alcohols as vehicles on the percutaneous absorption and skin retention of ibuprofen modified with l-valine alkyl esters

“…This results in loosening the lipid layer and increasing its uidity and consequently increases the degree of diffusion of active compounds. 59,63 Almost for each compound, there is the same tendency of an increase in the cumulative mass of ibuprofen that permeated through the skin, expressed as mg IBU cm À2 , with the change of the alcohol as a vehicle, in the sequence from methanol through ethanol to i-propanol, for both acceptors phases pH 5.4 and 7.4 (Table 4). It means, that i-propanol is the best enhancer of skin permeation of both unmodied ibuprofen and its salts with L- ).…”

Predicting in vivo absorption of chloramphenicol in frogs using in vitro percutaneous absorption data

“…As reduced exposure time would be of benefit in a clinical situation, the addition of 20%v/v PG as a penetration enhancer was considered to increase absorption rate. Our previous study reported a relationship between logP and the enhancement ratio (ER) for model chemicals when applied to the ventral pelvis in cane toads [ 36 ]. Thus, it is expected that the absorption rate from this formulation will increase according to this relationship.…”

“…Recently, we developed in vitro models of absorption in the cane toad ( Rhinella marina ) based on three model chemicals, and determined how well the models’ predictions of absorption matched the in vivo absorption of the same chemicals [ 35 ]. We have also reported the impact of penetration enhancers on absorption through frog skin [ 36 ]. The broad aim of this study is to determine the utility of these previous results in predicting the in vivo percutaneous absorption of a drug for treatment of infectious disease in frogs.…”

Can models of percutaneous absorption based on in vitro data in frogs predict in vivo absorption?

“…In addition to the masking effects of concurrent elimination processes occurring in vivo, the assumption that flux is constant from the start of dosing when predicting serum concentrations is another potential source of error. A lag-phase has only been reported in frog skin in vitro when the donor solution contains penetration enhancers [ 33 ]; as the first sample in the current study was taken at 30 minutes, it is possible that the lag phase occurred prior to this sample being taken. Disregarding even a short lag-time when predicting serum concentration would contribute to the disparity between in vitro predictions and in vivo concentrations.…”