酮洛芬异丙酯在离体裸小鼠和猴皮肤中的渗透和代谢

酮洛芬异丙酯在离体裸小鼠和猴皮肤中的渗透和代谢

朱全刚^*, 胡晋红

第二军医大学长海医院药学部, 上海 200433;

收稿日期:2002-09-09 修回日期:2003-02-10 出版日期:2003-03-15 发布日期:2003-03-15
通讯作者: 朱全刚*

Percutaneous Absorption and Metabolism of Ketoprofen Isopropyl Ester via Excised Nude Mouse's and Monkey's Skin

ZHU Quan-gang^*, HU Jin-hong

Department of Pharmacy, Changhai Hospital, Shanghai 200433, China

Received:2002-09-09 Revised:2003-02-10 Online:2003-03-15 Published:2003-03-15
Contact: ZHU Quan-gang*

摘要/Abstract

摘要： 目的研究酮洛芬异丙酯在离体裸小鼠和猴皮肤中的渗透和代谢, 阐明皮肤酯酶代谢的主要活性部位. 方法采用外科手术和酶消化方法制备离体皮肤, 用水平双室扩散池进行体外渗透实验, HPLC方法测定样品中的药物浓度. 结果经全皮和去角质层皮肤渗透的酮洛芬异丙酯被代谢成酮洛芬, 接受室中酮洛芬的浓度随时间延长而成线性增加.在裸小鼠皮肤中, 酮洛芬全皮渗透的稳态速率是酮洛芬异丙酯全皮渗透的2.5倍, 而渗透实验结束后酮洛芬异丙酯及代谢物酮洛芬在皮肤中残留量是酮洛芬渗透实验结束后残留量的22.2倍; 酮洛芬异丙酯经真皮渗透时, 代谢物酮洛芬的稳态形成速率大大小于经全皮渗透时的稳态形成速率.在猴皮肤中, 酮洛芬异丙酯经全皮渗透时代谢物酮洛芬的稳态形成速率是经去角质层皮肤的0.7倍, 而渗透实验结束后皮肤中酮洛芬和酮洛芬异丙酯的残留量是去角质层皮肤的2.0倍; 酮洛芬异丙酯经真皮渗透时, 代谢物酮洛芬的稳态形成速率小于经全皮和去角质层皮肤渗透时的稳态形成速率, 渗透结束后皮肤中酮洛芬的残留量也小. 结论酮洛芬酯前体药物在皮肤原位能被代谢成活性母体酮洛芬本身, 且在皮肤中能长时间驻留, 有助于提高和延长酮洛芬的局部疗效. 表皮层是皮肤酯酶代谢的主要活性部位.

关键词: 酮洛芬, 酮洛芬异丙酯, 经皮吸收, 皮肤代谢

Abstract: Aim To study percutaneous absorption and metabolism of ketoprofen isopropyl ester (KPE) via excised nude mouse’s and monkey’s skin. Methods Excised skin was prepared by surgical excision and enzyme digestion. Side-by-side diffusion cells were used for in vitro permeation studies. The concentrations of KPE and its metabolite in samples were assayed by HPLC. Results All KPE penetration through whole thickness skin and stripped skin was metabolized to ketoprofen (KP), the concentration of which in the receiver solution increased linearly with time. As to the nude mouse skin, the steady state flux of KP through whole thickness skin was 2-5 times that of KPE through the whole thickness skin, but the KP and KPE remaining in the whole thickness skin after the finishing of KPE penetration was 22-2 times in compared with the KP remaining in the whole thickness skin after the finishing of KP penetration. The rate of formation of the steady state KP from KPE through dermis was significantly lower than that of KPE through the whole thickness skin. In the monkey skin, the rate of formation of the steady-state KP from KPE through the whole thickness skin was 0-7 times that from KPE through stripped skin. The KP and KPE remaining in the whole thickness skin after the finishing of KPE penetration was 2-0 times that in the stripped skin after the finishing of KPE penetration. The rate of formation of the steady state KP from KPE through dermis was lower than that from KPE through the whole thickness skin and the stripped skin, the KP remaining in dermis after the finishing of KPE penetration was also significantly lower than the KP remaining in the whole thickness skin and the stripped skin after the finishing of KPE penetration. Conclusion KP esters are of benefit to improve the local action of KP, and skin esterase metabolism mainly develops in the epidermis.

Key words: ketoprofen, ketoprofen, ketoprofen isopropyl ester, ketoprofen isopropyl ester, skin permeation, skin permeation, skin metabolism, skin metabolism

中图分类号:

R965

Supporting: Foundation item: National Natural Science Foundation of China (39970880).
^*Corresponding author. Tel.: 86-21-25070674

朱全刚^*, 胡晋红. 酮洛芬异丙酯在离体裸小鼠和猴皮肤中的渗透和代谢[J]. .

ZHU Quan-gang^*, HU Jin-hong . Percutaneous Absorption and Metabolism of Ketoprofen Isopropyl Ester via Excised Nude Mouse's and Monkey's Skin[J]. .