薬物経皮吸収に及ぼす代謝の影響

—代謝過程を考慮した皮膚拡散モデルに基づく解析—

抄録

In vitro skin permeation study with rats was carried out to investigate the effect of cutaneous metabolism on the penetration of lipophilic drugs in the presence or absence of an esterase inhibitor, diisopropyl fluorophosphate (DFP). After the application of butylparaben, 96% of the total penetrated amount appeared as its hydrolyzed form (p-hydroxybenzoic acid) in the receiver fluid. On the other hand, in the case of propylparaben, the amount of the metabolite penetrated achieved approximately 70% of the total. When the skin was pretreated with 1 mM DFP, the appearance of the metabolite was completely inhibited. In addition, DFP significantly decreased the total penetration (the sum of intact and hydrolyzed forms) of butylparaben, but not that of propylparaben. The analysis based on a two-layer diffusion/metabolism model revealed that partitioning of butylparaben to the nonpolar route of stratum corneum was larger than that of propylparaben, and that DFP decreased the hydrolysis of parabens without altering their penetration parameters. This means that since butylparaben rapidly penetrates the stratum corneum, primarily due to its high lipophilicity, cutaneous metabolism process would dominate the total penetration of the drug. To comprehensively understand the relationship of skin penetration of drugs with their lipophilicities and metabolic rates, a simulation study using the diffusion/metabolism model was carried out. Total skin penetration of drug is larger as it is more lipophilic, and additionally increases as drug metabolism occurs. For more lipophilic drugs, the increase in total penetration associated with the metabolism becomes larger. This suggests that prodrugs having faster bioconversion rate to parent drug are more suitable for penetration enhancement.