Effect of oxidation of low-density lipoprotein on drug binding affinity studied by high performance frontal analysis-capillary electrophoresis

Citation
Y. Kuroda et al., Effect of oxidation of low-density lipoprotein on drug binding affinity studied by high performance frontal analysis-capillary electrophoresis, ELECTROPHOR, 22(16), 2001, pp. 3401-3407
Citations number
37
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Chemistry & Analysis
Journal title
ELECTROPHORESIS
ISSN journal
0173-0835 → ACNP
Volume
22
Issue
16
Year of publication
2001
Pages
3401 - 3407
Database
ISI
SICI code
0173-0835(200110)22:16<3401:EOOOLL>2.0.ZU;2-5
Abstract
The effect of oxidation of low-density lipoprotein (LDL) on the enantiosele ctive drug binding affinity was investigated using high performance frontal analysis - capillary electrophoresis (HPFA-CE). Verapamil and nivadipine e nantiomers were used as the chiral model drugs. LDL was oxidized with coppe r sulfate for 0, 0.5, 1, 2, and 12 h at 37 degreesC. The HPFA-CE method ena bled microdetermination of unbound drug concentrations in native and oxidiz ed LDL solutions. It was found that the bindings between LDL and the model drugs were not enantioselective at any oxidation stage. The total binding a ffinity (nK) between LDL and verapamil enantiomers was increased by 3.3-, 4 .6-, 7.0-, and 19-fold after 0.5, 1, 2, and 12 h oxidation, respectively, w hereas the nK value between nilvadipine and LDL was increased by 1.3-,1.4-, 1.4-, and 1.7-fold in the same reaction times, respectively. These results indicate that the LDL oxidation enhances the drug binding affinity, and the affinity of verapamil is increased more sensitively than that of nilvadipi ne. The nK value of each model drug increased steeply after the first 2 h o xidation, followed by the gradual increase after the next 10 h oxidation. I t is considered that the net increase in the negative charges and/or the fo rmation of hydroperoxides in the first 2 h oxidation enhances the drug-LDL binding more significantly than the formation of aldehydes or Schiff bases in the following 10 In oxidation.