Hasegawa Tetsuya, Kawazome Asako, Matsumoto Kaori, Yanagimoto Go, Hayashi Teruaki, Akimoto Masayuki, Todo Hiroaki, Sugibayashi Kenji
Faculty of Pharmaceutical Sciences, Josai International University, Togane, Chiba 283-8555, Japan.
Biol Pharm Bull. 2008 Jan;31(1):85-9. doi: 10.1248/bpb.31.85.
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.
在双琼脂凝胶盘植入的无毛大鼠中评估了局部应用的烟酸乙酯（EN）的皮肤处置和代谢情况。这种大鼠在腹部皮下植入两个琼脂凝胶盘作为药物受体，并通过皮肤在凝胶盘两侧放置含EN的局部制剂。在6小时内每2小时监测一次EN及其代谢产物烟酸（NA）的血浆和琼脂水平。EN透过皮肤屏障并部分代谢为NA，6小时时代谢产物比率[NA/（EN + NA）]为89.4%。皮肤中的一些EN和NA进入体循环，其余的则迁移到制剂下方的琼脂凝胶中。在6小时时，从制剂直接分布到体循环和凝胶应用侧的皮肤中总量（EN + NA）分别占皮肤总渗透量的95.2%和4.8%。只有NA从体循环分布到两个琼脂凝胶盘。从循环中进入凝胶应用侧的NA部分仅占琼脂凝胶中总量的1%。对于使用切除的无毛大鼠皮肤进行的体外皮肤渗透，琼脂凝胶应用侧的代谢产物比率高于接受侧。这种差异可能与原位活皮肤中EN比率低于体外有关。这些结果表明，目前的原位方法可用于评估局部应用药物的皮肤处置和代谢。
