Magnusson Beatrice M, Pugh W John, Roberts Michael S
Therapeutics Research Unit, Southern Clinical Division, University of Queensland, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia.
Pharm Res. 2004 Jun;21(6):1047-54. doi: 10.1023/b:pham.0000029295.38564.e1.
Simple rules based on readily accessible physicochemical properties enable identification of solutes that penetrate skin very slowly or rapidly.
Literature in vitro maximal flux values (Jmax) across human skin were collected for 87 penetrants. Penetrants were assigned as "good" (Jmax > 10(-5.52) mole x cm(-2) x h(-1)), "bad" (Jmax < 10(-8.84) mole x cm(-2) x h(-1)) or "intermediate" based on mean +/- 1SD. The feasibility of using readily available physicochemical properties, such as molecular weight (MW), melting point (MP, degrees K), octanol-water partition coefficient (K), water solubility (S, molarity), number of atoms available for H-bonding (HB), in assigning solutes was examined.
Good penetrants had MW < or = 152, log S > -2.3, HB < or = 5, log K < 2.6, MP < or = 432. Bad penetrants had MW > 213, log S < -1.6, HB > or = 4, log K > 1.2, MP > or = 223. Discriminant analysis using MW, HB, log K correctly assigned 70% of compounds. Individual success rates were good (88%), intermediate (58%), bad (93%). Aqueous Jmax data for 148 test solutes were used for validation. Discriminant analysis assigned 76% of compounds, with individual rates of good (76%), intermediate (67%), and bad (97%). No good penetrants were misclassified as bad or vice versa.
These rules enable rapid screening of potential drug delivery candidates and environmental exposure risks.
基于易于获取的物理化学性质的简单规则能够识别穿透皮肤非常缓慢或迅速的溶质。
收集了87种渗透剂在人皮肤上的体外文献最大通量值（Jmax）。根据平均值±1标准差，将渗透剂分为“良好”（Jmax > 10^(-5.52) 摩尔×厘米^(-2)×小时^(-1)）、“不良”（Jmax < 10^(-8.84) 摩尔×厘米^(-2)×小时^(-1)）或“中等”。研究了使用分子量（MW）、熔点（MP，开尔文度）、正辛醇-水分配系数（K）、水溶性（S，摩尔浓度）、可用于氢键结合的原子数（HB）等易于获得的物理化学性质来分类溶质的可行性。
良好渗透剂的MW ≤ 152，log S > -2.3，HB ≤ 5，log K < 2.6，MP ≤ 432。不良渗透剂的MW > 213，log S < -1.6，HB ≥ 4，log K > 1.2，MP ≥ 223。使用MW、HB、log K进行判别分析正确分类了70%的化合物。个体成功率分别为良好（88%）、中等（58%）、不良（93%）。148种测试溶质的水相Jmax数据用于验证。判别分析分类了76%的化合物，个体比例为良好（76%）、中等（67%）和不良（97%）。没有良好渗透剂被误分类为不良渗透剂，反之亦然。
这些规则能够快速筛选潜在的药物递送候选物和环境暴露风险。
