IN-VIVO EVALUATION OF ACYCLOVIR PRODRUG PENETRATION AND METABOLISM THROUGH RAT SKIN USING A DIFFUSION BIOCONVERSION MODEL/

Purpose. In order to evaluate the in vivo penetration of prodrugs whic h undergo metabolism in skin, we analyzed the in vivo penetration prof iles of acyclovir prodrugs based on a two-layer skin diffusion model i n consideration of metabolic process. Methods. Acyclovir prodrugs (e.g ., valerate, isovalerate and pivarate) were used as model prodrugs and the amounts excreted in urine were measured after percutaneous applic ation. In vivo penetration profiles were then estimated by employing a deconvolution method and the penetration of acyclovir prodrugs was an alyzed using a diffusion model. Subsequently, diffusion, partitioning and metabolic parameters were compared under in vitro and in vivo cond itions. Results, Although total penetration amounts at the end of the experiment were similar for the three prodrugs, the ratio of intact pr odrug to total penetration amount differed significantly. Moreover, th e excretion and absorption profiles were also very different for each prodrug. Enzymatic hydrolysis rate constants calculated under in vivo conditions were considerably larger than those obtained in the skin ho mogenate and in vitro penetration experiments. Conclusions, The presen t skin diffusion/bioconversion model combined with computer analysis e nables us to comprehensively account for diffusion, partitioning and m etabolism during in vivo percutaneous absorption. Nevertheless, differ ent enzymatic hydrolysis rate constants obtained under both in vivo an d in vitro conditions demonstrate the difficulty of obtaining accurate values for in vivo enzymatic activity from related in vitro experimen ts.