In vivo skin penetration enhancement of acyclovir by theoretical design of prodrug-enhancer combination

The effectiveness of prodrug-enhancer combination under in vivo skin penetration enhancement was studied using acyclovir and its lipophilic prodrugs, i.e. acyclovir valerate, isovalerate and pivarate together with an enhancer, 1-geranylazacycloheptan-2-one (GACH). Under in vivo penetration experiment with rat skin, we estimated absorption amounts of both prodrug and metabolized acyclovir respectively from the excretion amount by employing a deconvolution method. In the absence of GACH, the total amount of acyclovir absorbed at the end of 4 h experiment, after application of prodrug in the form of aqueous solution, was about twice than that obtained after administration of acyclovir itself. On the other hand, GACH showed slight absorption enhancement for acyclovir but demonstrated drastic enhancement effect on its prodrugs, especially valerate. Also, this enhancement effect was more remarkable under in vivo condition than in vitro one. Indeed, to elucidate the differences in enhancement effect among three prodrugs, we carried out some simulations to clarify the relationship among enhancement effect, lipophilicity of prodrugs and enzymatic hydrolysis rate constants. From the results of simulations, it was obviously noticed that metabolism only exerted an important effect on skin penetration of these prodrugs when applied with GACH simultaneously. Furthermore, according to this model analysis under in vivo condition, we came to understand that GACH significantly decreased the enzymatic activity in skin. Copyright (C) 1996 Elsevier Science B.V.