TEWL and Percutaneous Absorption: Influence of Compound Lipophilicity and Molecular Size

• Main Authors: Pi-Lien Hung, 洪碧蓮
• Other Authors: Jui-Chen Tsai
• Format: Others
• Language: zh-TW
• Published: 1999
• Online Access: http://ndltd.ncl.edu.tw/handle/12120032063951829153

碩士 === 國立成功大學 === 臨床藥學研究所 === 87 === The skin''s barrier function is important both to limit water loss and percutaneous absorption of environmental agents. Defined as the amount of water vapor passing the stratum corneum (SC) by passive diffusion, the measurement of transepidermal water loss (TEWL) has been used to study the water barrier function of both normal and diseased skin. In humans and animals, it has been demonstrated that, under physiological and pathological skin conditions, quantitative relationships exist between TEWL and percutaneous absorption for certain compounds. The goal of this study was to investigate the influence of compound lipophilicity and molecular size on the relationship between TEWL and percutaneous absorption. We utilized the techniques of acetone treatment on in vivo hairless mice to remove SC lipids, disrupt the permeability barrier to various TEWL levels, and examine the effects on percutaneous absorption in vitro. Sucrose (log Ko/w = -3.7), caffeine (log Ko/w = -0.02), hydrocortisone (log Ko/w = 1.5), estradiol (log Ko/w = 2.7), progesterone (log Ko/w = 3.9) and indomethacin (log Ko/w = 4.4) were used to establish the effects of lipophilicity. The influences of molecular size were studied using polyethylene glycols of molecular weight 300, 600, and 1000 as marker compounds. The results demonstrated that permeability barrier disruption by acetone treatment enhanced significantly the skin permeability of both hydrophilic and amphipathic compounds, including sucrose, caffeine and hydrocortisone. The treatment didn''t appear to alter the percutaneous penetration of highly lipophilic compounds, such as estradiol, progesterone, and indomethacin. The permeability enhancement seemed to increase with compound lipophilicity initially and decline afterwards. The effect was most prominent with hydrocortisone (log Ko/w = 1.5). A parabolic relationship exists between log P and log Ko/w at different degrees of permeability barrier disruption. The optimal log Ko/w of compound for skin penetration appeared to decrease with increase in TEWL levels. The maximal permeability achieved was similar through skin of different TEWL levels. Percutaneous penetration of PEGs exhibited a strong molecular weight dependency at the same TEWL levels, with more penetration of smaller oligomers than larger ones. When TEWL was elevated, the skin penetration of all the PEGs oligomers were enhanced, and the degree of enhancement was greater for the oligomer of molecular weight 370 daltons. Histochemical and electron microscopic examinations have revealed the reduction in SC lipid content and intercellular membrane structures by acetone treatment, with negligible changes in the number of horny layers. In addition, the SC/normal saline partition coefficients of water, caffeine and hydrocortisone were not increased with TEWL. We have concluded that the enhancement in skin permeability of both hydrophilic and amphipathic compounds was mainly due to the increase in SC diffusivity at higher TEWL levels.