Factors influencing isradipine and amlodipine binding to human plasma lipoproteins.

The objectives of this study were to determine the distribution of isradipine among individual plasma lipoproteins ex vivo in healthy volunteers (n = 8) and in hypercholesterolaemic patients (n = 12), and to investigate the mechanisms involved in the interaction of isradipine and amlodipine with isolated lipoprotein fractions in vitro. The distribution study ex vivo demonstrated the different relative affinity of isradipine for the plasma lipoproteins: high-density lipoprotein (HDL) > low-density lipoprotein (LDL) > very low-density lipoprotein (VLDL). Isradipine binding correlated linearly with the cholesterol levels in LDL and VLDL; however, binding to HDL did not correlate with the cholesterol level in this fraction. The total binding affinity of isradipine to isolated LDL was markedly higher compared with amlodipine; total binding affinity (nKa) of isradipine vs amlodipine was (1.60 +/- 0.08) x 10(7) l/mol vs (4.14 +/- 0.33) x 10(6) l/mol, respectively. Binding to HDL was also higher with isradipine --nKa = (1.04 +/- 0.04) x 10(5) l/mol--compared with that of amlodipine: nKa = (3.82 +/- 0.18) x 10(4) l/mol. There was no significant competitive binding effect of cyclosporin A (CyA) on isradipine binding to individual lipoprotein fractions. It is likely that, in addition to the structure of surface apoproteins, the factors determining the interaction of calcium antagonists with plasma lipoproteins also include the plasma level of each lipoprotein fraction as well as the lipophilicity of the drug.