Theoretical analysis of the effect of cutaneous metabolism on skin permeation of parabens based on a two-layer skin diffusion/metabolism model

The effect of cutaneous metabolism on the shin penetration of drugs was ana lyzed based on a two-layer skin diffusion/metabolism model. In vitro permea tion studies of propylparaben and butylparaben with or without an esterase inhibitor, diisopropyl fluorophosphate (DFP), were performed. Pretreatment of the skin with DFP prolonged the lag time for the penetration of intact p arabens, Additionally, DFP significantly decreased the total flux of butylp araben, but not that of propylparaben. Model analysis of the penetration pr ofiles revealed that DFP inhibits the cutaneous metabolism without affectin g any other processes. To comprehensively understand the relationships amon g lipophilicity; metabolic rate, and skin permeation of drugs, simulation s tudies were performed with newly derived equations concerning the permeabil ity coefficient and the lag time for the penetration of both intact and met abolite forms. The analysis revealed that the lag time for the penetration of both intact and metabolite forms becomes shorter with increasing metabol ic rate. As the metabolic rate of the drug increases, skin penetration of t he intact form decreases whereas that of the metabolite increases, The tota l flux of intact and metabolite forms increases with increasing metabolic r ate, being more obvious for highly lipophilic drugs. This indicates that th e permeation of lipophilic compounds such as butylparaben is more highly af fected by cutaneous metabolism in the viable layer because these compounds easily penetrate the stratum corneum layer. Consequently, the balance betwe en the permeability of drug across the stratum corneum and the dermis has b een implicated to impose a significant influence on the percutaneous absorp tion of drugs subjected to cutaneous metabolism.