Semmelweis University, Institute of Pharmaceutical Chemistry, Högyes Endre str. 9, H-1092 Budapest.
Chem Biodivers. 2009 Nov;6(11):1867-74. doi: 10.1002/cbdv.200900149.
There is a major need in drug discovery for quick, precise, and cost-effective high-throughput screening (HTS) systems in the early stages of drug research. The Parallel Artificial Membrane Permeability Assay (PAMPA) aims at predicting the passive membrane properties of drugs. Since 1998, model membranes have been developed to predict gastro-intestinal absorption or transport through the blood-brain barrier. This paper presents recent results in a project aiming to improve the prediction of transdermal penetration. Using the PAMPA system, we investigated the effect of four newly synthetized ceramide analogues (certramides) on the permeability of three model compounds (ciprofloxacin, nifedipine, and verapamil). The certramides differ in the length of one alkyl chain, while the other alkyl chain and the head group remained the same. A relationship between the membrane concentration of certramides (from 0 to 100%) and the permeability of compounds was found, and the results of different certramides were compared. The strongest effect on permeability was caused by the ceramide analogue CTR(C12-C16). The reproducibility of the experiments and the impact of presence or absence of organic solvents (dodecane and CHCl3) in the membrane were also investigated.
在药物研究的早期阶段，药物发现中非常需要快速、准确且具有成本效益的高通量筛选 (HTS) 系统。平行人工膜渗透性测定法 (PAMPA) 旨在预测药物的被动膜性质。自 1998 年以来，已经开发出模型膜来预测胃肠道吸收或通过血脑屏障的转运。本文介绍了旨在提高透皮渗透预测的项目中的最新结果。使用 PAMPA 系统，我们研究了四种新合成的神经酰胺类似物（神经酰胺）对三种模型化合物（环丙沙星、硝苯地平和维拉帕米）渗透性的影响。神经酰胺在一个烷基链的长度上有所不同，而另一个烷基链和头基保持不变。发现了神经酰胺的膜浓度（从 0 到 100%）与化合物渗透性之间的关系，并比较了不同神经酰胺的结果。对渗透性影响最大的是神经酰胺类似物 CTR(C12-C16)。还研究了实验的重现性以及膜中存在或不存在有机溶剂（十二烷和 CHCl3）的影响。
