A PREDICTIVE ALGORITHM FOR SKIN PERMEABILITY - THE EFFECTS OF MOLECULAR-SIZE AND HYDROGEN-BOND ACTIVITY
A PREDICTIVE ALGORITHM FOR SKIN PERMEABILITY - THE EFFECTS OF MOLECULAR-SIZE AND HYDROGEN-BOND ACTIVITY
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DOI：
10.1023/a:1016236932339
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发表时间：
1995-11-01
影响因子：
3.7
通讯作者：
GUY, RH
中科院分区：
文献类型：
--
作者：
POTTS, RO;GUY, RH
目的.开发一种基于分配扩散模型的非电解质通过皮肤转运的预测算法。药物渗透性由分配扩散方程描述。通过自由能关系，分配与药物的分子体积（MV）以及氢键供体（H-d）和受体（H-a）活性有关。使用基于脂质结构域内自由体积波动的通过脂质膜的扩散理论，扩散与药物的MV相关。这两个明确的描述相结合，给出一个方程描述渗透性的渗透剂的物理性质。用多元回归分析方法对37种非电解质的透水性进行了研究。回归分析的结果表明，数据中94%的变异性可以由仅包括渗透物的MV、H-d和H-a的模型来解释。这些结果进一步提供了基于这些参数的值来预测皮肤渗透性的算法。此外，各种化学官能团（例如，- COOH），并可单独从药物结构预测药物的经皮转运。通过人体皮肤的药物转运的生物药理学相关模型仅基于药物的物理性质而导出。该模型提供了一种根据药物结构和/或物理性质预测渗透性的算法。此外，该模型适用于一些脂质屏障膜，这表明在所有的一个共同的运输机制。
Purpose. To develop a predictive algorithm of nonelectrolyte transport through skin based upon a partitioning-diffusion model.Methods. Drug permeability is described by a partitioning-diffusion equation. Through free-energy relationships, partitioning is related to the drug's molecular volume (MV), and hydrogen bond donor (H-d) and acceptor (H-a) activity. Diffusion is related to the drug's MV using a theory of diffusion through lipid lamellae based on free-volume fluctuations within the lipid domain. These two explicit descriptions are combined to give an equation describing permeability in terms of the permeant's physical properties. The aqueous permeability coefficients of 37 nonelectrolytes through human epidermis were evaluated as a function of these physical properties using a multiple regression analysis.Result. The results of the regression analysis show that 94% of the variability in the data can be explained by a model which includes only the permeant's MV, H-d and H-a. These results further provide an algorithm to predict skin permeability based upon the values of these parameters. In addition, the relative contribution of various chemical functional groups (e.g., -COOH) is derived, and can be used to predict skin transport from drug structure alone.Conclusions. A biophysically relevant model of drug transport through human skin is derived based solely on the physical properties of the drug. The model provides an algorithm to predict permeability from the drug's structure andior physical properties. Moreover, the model is applicable to a number of lipid barrier membranes, suggesting a common transport mechanism in all.