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The skin disposition and metabolism of topically applied ethyl nicotinate (EN) were evaluated in dual agar gel disc-inserted hairless rats, which have two agar gel discs subcutaneously inserted into the abdominal region as drug receptors, and a topical formulation containing EN placed on either side of the gel disc through the skin. Plasma and agar levels of EN and its metabolite, nicotinic acid (NA), were followed every 2 h over 6 h. EN permeated through the skin barrier and partly metabolized to NA with 89.4% of the metabolite ratio [NA/(EN+NA)] at 6 h. Some EN and NA in the skin moved to the systemic circulation, and the remainder migrated into the agar gel below the formulation. The total amount (EN+NA) in the skin that distributed from the formulation directly to the systemic circulation and the application side of the gel corresponded to 95.2% and 4.8% of the total skin permeation at 6 h, respectively. Only NA was distributed from the systemic circulation to both agar gel discs. The NA fraction in the application side of the gel from the circulation was only 1% of the total amount in the agar gel. The metabolite ratio on the application side of the agar gel was higher than that in the receiver for the in vitro skin permeation using excised hairless rat skin. This difference was probably related to a lower EN ratio in viable skin in situ than in vitro. These results suggest that the present in situ method is useful to evaluate the skin disposition and metabolism of topically applied drugs.

Analysis of Skin Disposition and Metabolism of Ethyl Nicotinate after Topical Application Using Dual Agar Gel Disc-Inserted Rats