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The age-dependent characteristics of transdermal permeation of ethyl nicotinate (EN) and its metabolism to nicotinic acid (NA) were examined in rats at the ages of a fetus at 21 d, 3, 10, 50, 270 and 360 d. Skin transport in vitro was investigated using mounted skin in side-by-side diffusion chambers, and flux of EN and NA was determined. With developing and aging in rats, EN flux from EN-saturated solution declined gradually, however, NA flux increased drastically at 10 and 50 d. To elucidate the mechanism of this age-dependent escalation of NA flux, a hydrolysis study was performed using skin homogenate, and the Michaelis-Menten parameters (Vmax and Km) of EN were evaluated. Vmax and Vmax/Km ratio showed the same tendency with NA flux/total (EN+NA) flux ratio, suggesting that skin esterases in rats are developed gradually after birth, then increase markedly and become steady in the adult period. On the other hand, the affinity parameter, Km, was almost the same among all ages. Moreover, metabolic saturation of esterase during the transdermal process occurred in all ages, and maximal NA flux and EN concentration in the donor compartment for the maximal NA flux were also affected by age. These findings indicated that the discrepancy in transdermal profiles of EN among the ages tested was dominantly due to the difference in the development of esterase in the growth process.

Age Difference in Simultaneous Permeation and Metabolism of Ethyl Nicotinate in Rat Skin.