Species difference in simultaneous transport and metabolism of ethyl nicotinate in skin.

The objective of this research was to compare the characteristics of skin permeation and metabolism of ethyl nicotinate (EN) among humans and several animal models. In vitro simultaneous skin permeation and metabolism experiment of EN was done in side by side diffusion cells at 37 degrees C. An EN hydrolysis experiment was carried out using skin homogenate and kinetic parameters (Vmax and K(m)) were estimated by computer data-fitting to Michaelis-Menten equation. Both EN and a metabolite, nicotinic acid (NA), were detected in all receiver solutions in permeation studies and no significant chemical hydrolysis was found, indicating that enzymatic hydrolysis of EN occurred during the skin permeation process. Difference in total (EN + NA) flux, from EN-saturated solution, was less than double among various species. The ratio of NA flux to total flux was highest for rat (0.94) followed by hairless rat, mouse, human and hairless mouse (0.76, 0.23, 0.19 and 0.13), and thus a great species difference was found in skin esterase activity. Total flux increased linearly with increase in donor concentration for all species. For hairless rat, mouse and hairless mouse, NA fluxes increased with increase in EN donor concentration and reached a plateau, suggesting that metabolic saturation occurred in skin. Species difference in NA fluxes and EN donor concentration in which the NA flux reached a plateau were also found. In rats, kinetic parameters for EN hydrolysis using skin homogenate were significantly higher than those in mice. These results suggest that species difference in permeation profiles of EN might primarily reflect the difference in esterase activity. To predict skin permeability in human using an animal model, the species difference in skin metabolism should be taken into consideration.