Prediction of drug-membrane interactions by IAM-HPLC: effects of different phospholipid stationary phases on the partition of bases
Prediction of drug-membrane interactions by IAM-HPLC: effects of different phospholipid stationary phases on the partition of bases
复制标题
DOI：
10.1016/j.ejps.2004.03.019
复制
发表时间：
2004-07-01
影响因子：
4.6
通讯作者：
La Rotonda, MI
中科院分区：
文献类型：
--
作者：
Barbato, F;di Martino, G;La Rotonda, MI
采用固定化人工膜-磷脂酰胆碱-药物发现（IAM-PC-DD）高效液相色谱柱测定了39种中性和碱性化合物的色谱容量因子，并与已有的IAM-PC-MG柱的辛醇/水分配系数和容量因子进行了比较。这两个色谱柱的脂质相不同，因为IAM-PC-MG相是由生物膜中发现的磷脂酰胆碱组成的，而在IAM-PC-DD相中没有甘油连接物。我们发现，在不同的电离度下，这两相与碱性化合物的相互作用是不同的。在IAM-PC-MG柱上，离子化化合物与等亲性中性化合物一样或更强地保留。相反，它们在IAM-PC-DD柱上的保留力不如等亲性中性化合物，或者最多与等亲性中性化合物一样强。IAM-PC-MG数据似乎可以更好地预测药物与生物膜之间的相互作用。事实上，它们比IAM-PC-DD数据与生物膜和脂质体的分划有更好的相关性；此外，从文献来看，它们与生物活动的相关性更好。这些结果表明，即使是对IAM磷脂结构的适度修改也会对碱性化合物的保留产生重大影响。我们的结论是，一个可接受的IAM-HPLC估计生物膜和基本化合物之间的相互作用应该依赖于固定相，再现天然磷脂的结构。(C) 2004 Elsevier B.V.版权所有
The chromatographic capacity factors of 39 neutral and basic compounds were measured on an immobilized artificial membrane-phosphatidylcholine-drug discovery (IAM-PC-DD) HPLC column, and the values compared with both octanol/water partition coefficients and capacity factors previously obtained on an IAM-PC-MG column. These two columns differ in their lipidic phase, since the IAM-PC-MG phase is made of phosphatidylcholine as found in biomembranes, whereas the glycerol linker is absent in the IAM-PC-DD phase. We found that the two phases interact differently with basic compounds at different degrees of ionization. On the IAM-PC-MG column, ionized compounds are as strongly or more strongly retained than isolipophilic neutral compounds. In contrast, their retention on the IAM-PC-DD column is less strong than, or at most as strong as, that of isolipophilic neutral compounds. The IAM-PC-MG data appear as better predictors of the interactions between drugs and biological membranes. Indeed, they correlate better than the IAM-PC-DD data with partitioning in both biological membrane and liposomes; moreover, they are better correlated with biological activities from the literature. These results suggest that even modest modifications in the structure of IAM phospholipids can have a major effect on the retention of basic compounds. We conclude that an acceptable IAM-HPLC estimate of the interactions between biomembranes and basic compounds should rely on stationary phases that reproduce the structure of natural phospholipids. (C) 2004 Elsevier B.V. All rights reserved.