Nakamura Mayumi, Osakai Toshiyuki
Department of Chemistry, Graduate School of Science, Kobe University, Nada, Kobe 657-8501, Japan.
Eur J Pharm Sci. 2016 Aug 25;91:154-61. doi: 10.1016/j.ejps.2016.06.013. Epub 2016 Jun 19.
A digital simulation method has been developed for evaluating the membrane permeability of drugs in the parallel artificial membrane permeation assay (PAMPA). The simulation results have shown that the permeability coefficient (log Ppampa) of drugs is linearly increased with increasing their distribution coefficient (log KD,M) to the lipid membrane, i.e., the hydrophobicity of the drug molecules. However, log Ppampa shows signs of leveling off for highly hydrophobic drugs. Such a dependence of log Ppampa is in harmony with the reported experimental data, and has been well explained in terms of the change in the rate-determining step from the diffusion in the membrane to that in the unstirred water layer (UWL) on both sides of the membrane. Additionally, the effects of several factors, including lag time, diffusion coefficient, pH, and pKa, on the permeability coefficient have been well simulated. It has thus been suggested that the proposed method should be promising for in silico evaluation of the membrane permeability of drugs.
已经开发出一种数字模拟方法，用于在平行人工膜渗透试验（PAMPA）中评估药物的膜渗透性。模拟结果表明，药物的渗透系数（log Ppampa）随着其在脂质膜中的分配系数（log KD,M）增加而线性增加，即药物分子的疏水性增加。然而，对于高疏水性药物，log Ppampa显示出趋于平稳的迹象。log Ppampa的这种依赖性与报道的实验数据一致，并且已根据速率决定步骤从膜中的扩散转变为膜两侧未搅拌水层（UWL）中的扩散得到了很好的解释。此外，还很好地模拟了包括滞后时间、扩散系数、pH和pKa在内的几个因素对渗透系数的影响。因此，有人提出所提出的方法在药物膜渗透性的计算机模拟评估方面应该很有前景。
