Pharmacokinetic modeling and penetration enhancement of the percutaneous drug absorption based on diffusion theory

建立了两层皮肤模型，分别考虑第一层角质层和第二层真皮，角质层具有极性和非极性两种途径，并由Fick扩散定律推导出无限剂量和有限剂量系统中相应的变换方程。通过快速反拉普拉斯变换(FILT)算法将这些图像方程逆变换到实时过程，从物理化学的角度分析药物的吸收行为。利用该系统考察了不同剂量的1-香叶基-氮杂环庚酮(GACH)对7种不同脂类药物体外经皮渗透的影响，并从药物在各部位的分配和扩散性等方面探讨了其作用机理。提示GACH主要通过改变角质层作为溶剂的性质而影响角质层的非极性途径。此外，还分析了d-柠檬烯和油酸对药物吸收的影响，认为它们通过增加药物在角质层中的扩散系数来促进药物的吸收。建立了与体内条件相对应的皮肤扩散模型，并在此基础上讨论了体内外数据之间的关系。

Two-layer skin model considering the first stratum corneum layer with polar and nonpolar routes and the second viable epidermis plus dermis layer was constructed and the corresponding transformed equations in the infinite and finite dose systems were derived from the Fick's diffusion low. By employing the inversion of these image equations to the real time course by the fast inverse Laplace transform(FILT)algorithm, absorption behavior of drugs were analyzed from physicochemical viewpoint. Using this system, the effects of different doses of 1-geranyl-azacycloheptan-2-one(GACH)on the in vitro penetration of seven drugs with various lipophilicities through the guinea pig skin were examined and its action mechanism wasdiscussed in terms of the partitioning and diffusivity of drugs in each domain. It was suggested that GACH mainly affects on the nonpolar route of the stratum corneum by changing its property as a solvent. The effects of d-limonen and oleic acid were also analyzed and the were concluded to enhance drug absorption by increasing the diffusivity of the drug in the stratum corneum. A skin diffusion model corresponding to in vivo condition was also constructed and relationship between in vitro and in vivo data was discussed based on these models.