Effect of barrier disruption by acetone treatment on the permeability of compounds with various lipophilicities: Implications for the permeability of compromised skin
Effect of barrier disruption by acetone treatment on the permeability of compounds with various lipophilicities: Implications for the permeability of compromised skin
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DOI：
10.1002/jps.1077
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发表时间：
2001-09-01
影响因子：
3.8
通讯作者：
Cheng, CL
中科院分区：
文献类型：
--
作者：
Tsai, JC;Sheu, HM;Cheng, CL
用丙酮破坏的无毛小鼠皮肤作为模型膜，研究受损皮肤屏障的渗透性。以蔗糖、咖啡因、氢化可的松、雌二醇和孕酮为模型化合物，研究了化合物亲脂性的影响。结果表明，渗透屏障破坏丙酮处理显着提高了皮肤的渗透性，亲水性和两亲性化合物，包括蔗糖，咖啡因和氢化可的松。在不同的经表皮水分损失（TEWL）水平下，咖啡因和氢化可的松的这种效果更为突出。然而，丙酮处理似乎没有改变高亲脂性化合物（如雌二醇和孕酮）的经皮渗透。在不同渗透屏障破坏程度下，皮肤渗透性特征可用log P-WS（全皮肤渗透系数）与log K-O/W（辛醇/水分配系数）之间的抛物线关系来描述。皮肤渗透的化合物的最佳log K-O/W似乎随着TEWL水平的增加而降低。通过显示不同TEWL水平的皮肤实现的最大渗透性相似。在尝试探索皮肤渗透性变化的潜在机制时，水、咖啡因和氢化可的松的角质层/生理盐水分配系数随着TEWL的增加而降低或保持不受影响。电子显微镜检查显示，丙酮处理的结果角质层脂质含量和细胞间膜结构的改变减少，而角质层的番红染色观察到的角质层的数量可以忽略不计的变化。我们得出的结论是，通过丙酮处理，皮肤对亲水性和两亲性化合物的渗透性的增强主要是因为在较高的TEWL水平下角质层扩散率的增加。这些结果意味着使用TEWL和药物亲脂性来预测皮肤渗透性的改变，从而为皮肤屏障功能受损的患者调整局部应用药物的剂量。(C)2001 Wiley-Liss，Inc.和美国制药协会。
The permeability of compromised skin barrier was investigated in vitro using acetone-disrupted hairless mouse skin as a model membrane. The effect of compound lipophilicity was studied using sucrose, caffeine, hydrocortisone, estradiol, and progesterone as model compounds. The results demonstrated that permeability barrier disruption by acetone treatment significantly enhanced the permeability of the skin to both hydrophilic and amphipathic compounds, including sucrose, caffeine and hydrocortisone. This effect was more prominent with caffeine and hydrocortisone at different transepidermal water loss (TEWL) levels. Acetone treatment, however, didn't appear to alter the percutaneous penetration of highly lipophilic compounds, such as estradiol and progesterone. The characteristics of skin permeability were described by parabolic relationships between log P-WS (permeability coefficient of whole skin) and log K-O/W (octanol/water partition coefficient) at different degrees of permeability barrier disruption. The optimal log K-O/W of compounds for skin penetration appeared to decrease with an increase in TEWL levels. The maximal permeability achieved was similar through skin displaying different TEWL levels. In an attempt to explore the underlying mechanisms for the changes in skin permeability, the stratum corneum/ normal saline partition coefficients of water, caffeine, and hydrocortisone either decreased or remained unaffected with an increase in TEWL. Electron microscopic examinations have revealed reductions in stratum corneum lipid content and alterations in intercellular membrane structures as a result of acetone treatment, whereas negligible changes in the number of horny layers were observed by safranin staining of the stratum corneum. We have concluded that the enhancement in skin permeability to both hydrophilic and amphipathic compounds by acetone treatment arose mainly because of the increase in stratum corneum diffusivity at higher TEWL levels. The results imply the possibility of using both TEWL and drug lipophilicity to predict alterations in skin permeability and hence the dose adjustment of topically applied medication for patients with impaired skin barrier function. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association.