ANALYSIS OF IN-VITRO SKIN PENETRATION OF ACYCLOVIR PRODRUGS BASED ON A DIFFUSION-MODEL WITH A METABOLIC PROCESS

The penetration of seven acyclovir prodrugs through the rat skin with or without an enhancer, 1-geranylazacycloheptan-2-one (GACH), was anal yzed based on a newly developed two-layer skin diffusion model with po lar and nonpolar routes in the stratum corneum including metabolic pro cess. The Laplace-transformed equations for prodrug and regenerated ac yclovir were derived from Fick's second law assuming first-order hydro lysis and were fitted to the experimental data. Under the condition wi thout GACH treatment, more lipophilic prodrugs gave higher partition p arameters in the nonpolar route. The enzymatic hydrolysis rate constan ts estimated by the model analysis of the penetration experiment were basically similar in rank order to those obtained using skin homogenat e. Concerning the effect of GACH, the estimated partition parameters o f prodrugs in the nonpolar route increased with an increase in pretrea tment 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.