Identification and analysis of stereoselective drug interactions with low-density lipoprotein by high-performance affinity chromatography.

ABSTRACT: Columns containing immobilized low-density lipoprotein (LDL) were prepared for the analysis of drug interactions with this agent by high-performance affinity chromatography (HPAC). R/S-Propranolol was used as a model drug for this study. The LDL columns gave reproducible binding to propranolol over 60 h of continuous use in the presence of pH 7.4 0.067 M potassium phosphate buffer. Experiments conducted with this type of column through frontal analysis indicated that two types of interactions were occurring between R-propranolol and LDL, while only a single type of interaction was observed between S-propranolol and LDL. The first type of interaction, which was seen for both enantiomers, involved non-saturable binding; this interaction had an overall affinity (nK(a)) of 1.9 (±0.1) × 10(5) M(-1) for R-propranolol and 2.7 (±0.2) × 10(5) M(-1) for S-propranolol at 37 °C. The second type of interaction was observed only for R-propranolol and involved saturable binding that had an association equilibrium constant (K(a)) of 5.2 (±2.3) × 10(5) M(-1) at 37 °C. Similar differences in binding behavior were found for the two enantiomers at 20 °C and 27 °C. This is the first known example of stereoselective binding of drugs by LDL or other lipoproteins. This work also illustrates the ability of HPAC to be used as a tool for characterizing mixed-mode interactions that involve LDL and related binding agents.

SUBMITTER: Sobansky MR 

PROVIDER: S-EPMC3315835 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature