IN-VIVO SKIN PENETRATION ENHANCEMENT OF ACYCLOVIR BY THEORETICAL DESIGN OF PRODRUG-ENHANCER COMBINATION

The effectiveness of prodrug-enhancer combination under in vivo skin p enetration enhancement was studied using acyclovir and its lipophilic prodrugs, i.e. acyclovir valerate, isovalerate and pivarate together w ith an enhancer, 1-geranylazacycloheptan-2-one (GACH). Under in vivo p enetration experiment with rat skin, we estimated absorption amounts o f both prodrug and metabolized acyclovir respectively from the excreti on 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 abou t twice than that obtained after administration of acyclovir itself. O n the other hand, GACH showed slight absorption enhancement for acyclo vir but demonstrated drastic enhancement effect on its prodrugs, espec ially valerate. Also, this enhancement effect was more remarkable unde r in vivo condition than in vitro one. Indeed, to elucidate the differ ences in enhancement effect among three prodrugs, we carried out some simulations to clarify the relationship among enhancement effect, lipo philicity of prodrugs and enzymatic hydrolysis rate constants. From th e results of simulations, it was obviously noticed that metabolism onl y exerted an important effect on skin penetration of these prodrugs wh en applied with GACH simultaneously. Furthermore, according to this mo del 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.