The effects of several penetration-enhancers on the simultaneous transport and metabolism of ethyl nicotinate in hairless rat skin

Abstract

The effects of enhancers such as Azone, L-menthol, ethanol and the l-menthol-ethanol-water (MEW) system on the simultaneous transport and metabolism of ethyl nicotinate (EN) through excised hairless rat skin were measured. The sum of the skin permeability coefficients of EN and its metabolite, nicotinic acid (NA), was utilized to assess their penetration-enhancement abilities, and the flux ratio of NA against the total (EN + NA) flux was used as a metabolic index to evaluate the effect of the enhancers on the skin metabolism of EN. The addition of 1% l-menthol increased the total skin permeability coefficient to about 2.5 times that of the control (without l-menthol), whereas 40% ethanol decreased this coefficient. This was probably due to the lowered thermodynamic activity of EN in the vehicle caused by the addition of ethanol. The simultaneous use of l-menthol and ethanol (MEW system) showed a similar permeability coefficient to that of the control. This may be explained by the decreased activity of EN caused by ethanol and by the increased diffusivity of the skin caused by l-menthol. All of the enhancers decreased the metabolic index in hairless rat skin, compared to the control. The reversibility of this index was then evaluated with a pretreatment experiment of the enhancers. The metabolic activity from EN to NA in skin was immediately recovered after the removal of ethanol, l-menthol or MEW system. The penetration-enhancing effect resulting from 1% l-menthol pretreatment was lower than that resulting from MEW pretreatment or 3% Azone pretreatment. With respect to the metabolic index recovery rate in skin, l-menthol may be much safer than Azone. l-Menthol, ethanol and the MEW system are therefore safe and effective ways to enhance or control skin permeation and to decrease the skin metabolism of prodrugs and peptides which are easily bioconverted in skin.