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

Purpose. To study the in vitro distribution of the enantiomers of theantimalarial drug halofantrine in human, dog and rat plasmalipoprotein-fractions.Methods. Plasma was spiked with racemic halofantrine (1000 ng/ml)and incubated for 1 h at 37°C. The fractions (high and low densitylipoproteins, triglyceride-rich lipoproteins and lipoprotein deficientplasma) were separated using density gradient ultracentrifugation.Fractions were assayed for halofantrine enantiomer using stereospecifichigh performance liquid chromatography.Results. The (−) enantiomer of halofantrine displayed higher affinityfor the lipoprotein-deficient fraction than the (+) enantiomer in allthree species. The (+) enantiomer was predominately located in thelipoprotein rich fractions of dog and human plasma (the (+):(−) ratioranging from 1.2–9.6). In contrast, the (+):(−) ratio was consistently<1 in lipoprotein-deficient fractions. Dog displayed a large magnitudeof stereoselectivity in halofantrine distribution to the plasma fractionstested. There were substantial interspecies differences in the pattern ofdistribution of halofantrine enantiomers within the different fractions. Asignificant positive relationship was observed between halofantrineuptake into lipoprotein-rich fractions and the percent of apolar corelipid in those fractions. There was also a strong negative correlationbetween total protein concentration and the enantiomeric ratio in thelipoprotein-deficient plasma fraction.Conclusion. Distribution of halofantrine enantiomer to plasma lipoprotein-fractions is stereoselective and species specific. This differentialbinding of halofantrine enantiomers to lipoproteins may need to beconsidered in viewing pharmacokinetic and pharmacodynamic datainvolving the drug.