ANALYSIS OF SIMULTANEOUS TRANSPORT AND METABOLISM OF ETHYL NICOTINATEIN HAIRLESS RAT SKIN

Purpose Simultaneous skin transport and metabolism of ethyl nicotinate (EN), a model drug, were measured and theoretically analyzed. Methods . Several permeation studies of EN or its metabolite nicotinic acid (N A) were done on full-thickness skin or stripped skin with and without an esterase inhibitor. Permeation parameters such as partition coeffic ient of EN from the donor solution to the stratum corneum and diffusio n coefficients of EN and NA in the stratum corneum and the viable epid ermis and dermis were determined by these studies. Enzymatic parameter s (Michaelis constant K-m and maximum metabolism rate V-max) were obta ined from the production rate of NA from different concentrations of E N in the skin homogenate. Obtained permeation data were then analyzed by numerical method based on differential equations showing Fick's sec ond law of diffusion in the stratum corneum and the law with Michaelis -Menten metabolism in the viable epidermis and dermis. Results, Fairly good steady-state fluxes of EN and NA through the skin were obtained after a short lag time for all the concentrations of EN applied. These steady-state fluxes were not proportional to the initial donor concen tration of EN: EN and NA curves were concave and convex, respectively, which suggests that metabolic saturation from EN to NA takes place in the viable skin at higher EN application. The steady-state fluxes of EN and NA calculated by the differential equations with resulting perm eation and enzymatic parameters were very close to the obtained data. Conclusions. The present method is a useful tool to analyze simultaneo us transport and metabolism of many drugs and prodrugs, especially tho se showing Michaelis-Menten type-metabolic saturation in skin.