Analysis of in vitro skin penetration of acyclovir prodrugs based on a diffusion model with a metabolic process

被引:21
作者
Bando, H [1 ]
Sahashi, M [1 ]
Takagi, T [1 ]
Yamashita, F [1 ]
Takakura, Y [1 ]
Hashida, M [1 ]
机构
[1] KYOTO UNIV, FAC PHARMACEUT SCI, DEPT DRUG DELIVERY RES, SAKYO KU, KYOTO 60601, JAPAN
关键词
percutaneous absorption; acyclovir; acyclovir prodrug; enhancer treatment; metabolism; diffusion model;
D O I
10.1016/0378-5173(96)85199-4
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The penetration of seven acyclovir prodrugs through the rat skin with or without an enhancer, 1-geranylazacycloheptan-2-one (GACH), was analyzed based on a newly developed two-layer skin diffusion model with polar and nonpolar routes in the stratum corneum including metabolic process. The Laplace-transformed equations for prodrug and regenerated acyclovir were derived from Fick's second law assuming first-order hydrolysis and were fitted to the experimental data. Under the condition without GACH treatment, more lipophilic prodrugs gave higher partition parameters in the nonpolar route. The enzymatic hydrolysis rate constants estimated by the model analysis of the penetration experiment were basically similar in rank order to those obtained using skin homogenate. Concerning the effect of GACH, the estimated partition parameters of prodrugs in the nonpolar route increased with an increase in pretreatment dose of GACH, but their diffusivities were little affected being in good agreement with the theoretical prediction. In addition, GACH significantly decreased the enzymatic hydrolysis rate constants of all prodrugs in the skin.
引用
收藏
页码:91 / 102
页数:12
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