Quantitative structure-activity relationships studies with micellar electrokinetic chromatography. Influence of surfactant type and mixed micelles on estimation of hydrophobicity and bioavailability.

Abstract

Applications of micellar electrokinetic chromatography (MEKC) in quantitative structure-activity relationships (QSAR) were studied. First, quantitative structure-retention relationships (QSRR), which describe the correlation between logarithm of capacity factor (log k') in MEKC and logarithm of distribution coefficient between 1-octanol and water (log P(ow)), were investigated for 60 aromatic compounds and 9 corticosteroids using three different anionic surfactants [e.g., sodium dodecyl sulfate (SDS), sodium cholate (SC), and lithium perfluorooctane sulfonate (LiPFOS)], one cationic surfactant (C14TAB), and mixed anionic micellar systems. Linear solvation energy relationships (LSER) and solvatochromic parameters were used to shed light on the different log k' vs. log P(ow) relationships of the various surfactants. It was concluded that hydrogen bonding interactions have a great influence on retention behavior in MEKC and its relationships with hydrophobicity. Interestingly, bile salt surfactants (e.g., SC) and mixed bile salt micellar systems provide better correlations for log k' vs. log P(ow) than SDS and/or SDS with buffer additives (e.g., beta-cyclodextrin, urea, and acetonitrile). Using SC micelles, only one line was adequate to describe the relationship between retention in MEKC and hydrophobicity for a group of 60 aromatic compounds. The existence of higher correlation for the SC system was attributed to a similar hydrogen bonding pattern between SC micelles and 1-octanol. In the SDS system, however, three lines were recognized for the congeneric subgroups of compounds. This is due to the hydrogen bond door (HBD) characteristic of SDS micelles that selectively differentiate between the solutes with different hydrogen bond acceptor (HBA) strength, thus demonstrating that retention is not solely based on hydrophobicity. A similar result was observed for a C14TAB-MEKC system, however, the HBA characteristic of C14TAB selectively differentiates between the solutes with different HBD strength. In addition, quantitative retention-activity relationships in MEKC were also investigated for 9 corticosteroids. Two types of biological activities [small intestinal absorption in the rat (log A/NA) and protein binding to human serum albumin (log B/F) were examined in this work. High correlations were observed between bioactivity and log k' in MEKC using bile salt surfactants and mixed bile salt systems.