DIFFERENCES IN LIPOPROTEIN LIPID-CONCENTRATION AND COMPOSITION MODIFYTHE PLASMA DISTRIBUTION OF CYCLOSPORINE

Purpose. The purpose of this study was to define the relationship betw een lipoprotein (LP) lipid concentration and composition and the distr ibution of cyclosporine (CSA) in human plasma. Methods, H-3-CSA LP dis tribution was determined in normolipidemic human plasma that had been separated into different LP and lipoprotein-deficient plasma (LPDP) fr actions by either affinity chromatography coupled with ultracentrifuga tion, density gradient ultracentrifugation or fast protein liquid chro matography. 3H-CSA LP distribution (at a concentration of 1000 ng/ml) was also determined in patient plasma samples with defined dyslipidemi as. Furthermore, 3H-CSA LP distribution was determined in patient plas ma samples of varying LP lipid concentrations. Following incubation, t he plasma samples were separated into their LP and LPDP fractions by s equential phosphotungistic acid precipitation in the dyslipidemia stud ies 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) conc entrations 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 simila r with most of the drug bound to plasma high-density (HDL) and low-den sity (LDL) lipoproteins. When H-3-CSA was incubated in dyslipidemic hu man plasma or specific patient plasma of varying LP lipid concentratio ns 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 increas ed. The percent of CSA recovered within the HDL fraction significantly decreased as HDL triglyceride concentrations increased. The percent o f CSA recovered in the LPDP fraction remained constant except in hyper cholesterolemic/hypertriglyceridemic plasma where the percent of CSA r ecovered 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 an d plasma LP lipid concentration and composition influence the LP bindi ng of CSA and may explain differences in the pharmacological activity and toxicity of CSA when administered to patients with different lipid profiles.