The stereoselective distribution of halofantrine enantiomers within human,dog, and rat plasma lipoproteins

Purpose. To study the in vitro distribution of the enantiomers of the antim alarial drug halofantrine in human, dog and rat plasma lipoprotein-fraction s. Methods. Plasma was spiked with racemic halofantrine (1000 ng/ml) and incub ated for 1 h at 37 degrees C. The fractions (high and low density lipoprote ins, triglyceride-rich lipoproteins and lipoprotein deficient plasma) were separated using density gradient ultracentrifugation. Fractions were assaye d for halofantrine enantiomer using stereospecific high performance liquid chromatography. Results. The (-) enantiomer of halofantrine displayed higher affinity for t he lipoprotein-deficient fraction than the (+) enantiomer in all three spec ies. The (+) enantiomer was predominately located in the lipoprotein rich f ractions of dog and human plasma (the (+):(-) ratio ranging from 1.2-9.6). In contrast, the (+):(-) ratio was consistently <1 in lipoprotein-deficient fractions. Dog displayed a large magnitude of stereoselectivity in halofan trine distribution to the plasma fractions tested. There were substantial i nterspecies differences in the pattern of distribution of halofantrine enan tiomers within the different fractions. A significant positive relationship was observed between halofantrine uptake into lipoprotein-rich fractions a nd the percent of apolar core lipid in those fractions. There was also a st rong negative correlation between total protein concentration and the enant iomeric ratio in the lipoprotein-deficient plasma fraction. Conclusion. Distribution of halofantrine enantiomer to plasma lipoprotein-f ractions is stereoselective and species specific. This differential binding of halofantrine enantiomers to lipoproteins may need to be considered in v iewing pharmacokinetic and pharmacodynamic data involving the drug.