Poulin P, Krishnan K
Groupe de Recherche en Toxicologie Humaine (TOXHUM), Université de Montréal, Canada.
J Toxicol Environ Health A. 2001 Feb 9;62(3):143-59. doi: 10.1080/009841001458271.
Mechanistically based predictions of skin permeability coefficients (Kp) derived solely on the basis of molecular structure information of organic compounds have not been reported previously. The objective of the present study was to predict the human abdominal Kp of structurally unrelated organic compounds using a mechanistic equation that takes into account compound-specific and species-specific determinants of Kp and relates the compound-specific determinants directly to molecular structure information. The method consisted of obtaining predictions based on a modified form of the conventional equation used to describe Kp (= P x D/L, where P, D, and L represent the stratum corneum:water partition coefficient, diffusion coefficient, and path length of diffusion). The value of P was predicted from the n-octanol:water partition coefficient (Po:w) computed from molecular structure information as well as the lipid, protein, and water contents in stratum corneum. The value of D was predicted according to the conventional Einstein-Stoke equation using the molar volume (Vmolar) of compounds computed from molecular structure information as well as data on viscosity of the stratum corneum components. Finally, the value of L was estimated in accordance with the characteristics of the diffusion pathways in the stratum corneum (i.e., transcellular and intercellular pathways). The average ratio of predicted Kp to the corresponding mean experimental values obtained from the literature was 1.25 (SD = 0.68, r = .95) for 47 structurally unrelated organic compounds (volatile organics and drugs), which were characterized by the presence of less than 2 hydrogen bonding groups and Vmolar < 231 cm3/mol. The present study is the first initiative that permits prediction of the human Kp of organic compounds by using molecular structure information as the sole chemical-specific input in a mechanistic equation.
以往尚未有仅基于有机化合物分子结构信息对皮肤渗透系数（Kp）进行基于机制的预测的报道。本研究的目的是使用一个机制方程来预测结构不相关的有机化合物的人体腹部Kp，该方程考虑了Kp的化合物特异性和物种特异性决定因素，并将化合物特异性决定因素直接与分子结构信息相关联。该方法包括基于用于描述Kp的传统方程的修改形式进行预测（Kp = P×D/L，其中P、D和L分别代表角质层：水分配系数、扩散系数和扩散路径长度）。P的值根据从分子结构信息计算得到的正辛醇：水分配系数（Po:w）以及角质层中的脂质、蛋白质和水含量进行预测。D的值根据传统的爱因斯坦-斯托克斯方程，使用从分子结构信息计算得到的化合物摩尔体积（Vmolar）以及角质层成分的粘度数据进行预测。最后，根据角质层中扩散途径的特征（即跨细胞和细胞间途径）估计L的值。对于47种结构不相关的有机化合物（挥发性有机物和药物），预测的Kp与从文献中获得的相应平均实验值的平均比值为1.25（标准差 = 0.68，r = 0.95），这些化合物的特征是存在少于2个氢键基团且Vmolar < 231 cm³/mol。本研究是首次通过在机制方程中使用分子结构信息作为唯一的化学特异性输入来预测有机化合物人体Kp的尝试。
