Differences in the lipoprotein distribution of halofantrine are regulated by lipoprotein apolar lipid and protein concentration and lipid transfer protein I activity: In vitro studies in normolipidemic and dyslipidemic human plasmas

The purpose of these studies was to determine the distribution of a lipophilic antimalarial agent, halofantrine hydrochloride (Hf), in fasted plasma from hypo‐, normo‐, and hyperlipidemic patients that displayed differences in lipoprotein concentration and lipid transfer protein I (LTP I) activity. To assess the influence of modified lipoprotein concentrations and LTP I activity on the plasma distribution of Hf, Hf at a concentration of 1000 ng/mL was incubated in either hypo‐, normo‐, or hyperlipidemic human plasma for 1 h at 37 °C. Following incubation, the plasma samples were separated into their lipoprotein and lipoprotein‐deficient plasma (LPDP) fractions by density gradient ultracentrifugation and assayed for Hf by high‐pressure liquid chromatography. The activity of LTP I in the dyslipidemic plasma samples was determined in terms of its ability to transfer cholesteryl ester from low‐density lipoproteins (LDL) to high‐density lipoproteins (HDL). Total plasma and lipoprotein cholesterol (esterified and unesterified), triglyceride, and protein levels in the dyslipidemic plasma samples were determined by enzymatic assays. When Hf was incubated in normolipidemic plasma for 1 h at 37 °, the majority of drug was found in the LPDP fraction. When Hf was incubated in human plasma of varying total lipid, lipoprotein lipid, and protein concentrations and LTP I activity, the following relationships were observed. As the triglyceride‐rich lipoprotein (TRL) lipid and protein concentration increased from hypolipidemia through to hyperlipidemia, the proportion of Hf associated with TRL increased (r > 0.90). As the HDL lipid and protein concentration increased, the proportion of Hf associated with HDL decreased (r > 0.70). As the total and lipoprotein lipid levels increased, the LTP I activity of the plasma also proportionally increased (r > 0.85). Furthermore, with the increase in LTP I activity, the proportion of Hf associated with the TRL fraction increased (r > 0.70) and the proportion of Hf associated with the HDL fraction decreased (r > 0.80). In addition, a positive correlation between the proportion of apolar lipid and Hf recovered within each lipoprotein fraction was observed within hypo‐ (r > 0.80), normo‐ (r = 0.70), and hyperlipidemic (r > 0.90) plasmas. These findings suggest that changes in the HDL and TRL lipid and protein concentrations, LTP I activity, and the proportion of apolar lipid within each lipoprotein fraction may influence the plasma lipoprotein distribution of Hf in dyslipidemia.