Purpose: The purpose of this study was to define the relationship between lipoprotein (LP) lipid concentration and composition and the distribution of cyclosporine (CSA) in human plasma.
Methods: 3H-CSA LP distribution was determined in normolipidemic human plasma that had been separated into different LP and lipoprotein-deficient plasma (LPDP) fractions by either affinity chromatography coupled with ultracentrifugation, density gradient ultracentrifugation or fast protein liquid chromatography. 3H-CSA LP distribution (at a concentration of 1000 ng/ml) was also determined in patient plasma samples with defined dyslipidemias. Furthermore, 3H-CSA LP distribution was determined in patient plasma samples of varying LP lipid concentrations. Following incubation, the plasma samples were separated into their LP and LPDP fractions by sequential phosphotungistic acid precipitation in the dyslipidemia studies and by density gradient ultracentrifugation in the specific lipid profile studies and assayed for CSA by radioactivity. Total plasma and lipoprotein cholesterol (TC), triglyceride (TG) and protein (TP) concentrations in each sample were determined by enzymatic assays.
Results: When the LP distribution of CSA was determined using three different LP separation techniques, the percent of CSA recovered in the LP-rich fraction was greater than 90% and the LP binding profiles were similar with most of the drug bound to plasma high-density (HDL) and low-density (LDL) lipoproteins. When 3H-CSA was incubated in dyslipidemic human plasma or specific patient plasma of varying LP lipid concentrations the following relationships were observed. As the very low-density (VLDL) and LDL cholesterol and triglyceride concentrations increased, the percent of CSA recovered within the VLDL and LDL fractions increased. The percent of CSA recovered within the HDL fraction significantly decreased as HDL triglyceride concentrations increased. The percent of CSA recovered in the LPDP fraction remained constant except in hypercholesterolemic/hypertriglyceridemic plasma where the percent of CSA recovered decreased. Furthermore, increases in VLDL and HDL TG/TC ratio resulted in a greater percentage of CSA recovered in VLDL but less in HDL.
Conclusions: These findings suggest that changes in the total and plasma LP lipid concentration and composition influence the LP binding of CSA and may explain differences in the pharmacological activity and toxicity of CSA when administered to patients with different lipid profiles.