title: The stereoselective distribution of halofantrine enantiomers within human, dog, and rat plasma lipoproteins.
abstract: OBJECTIVE
  To study the in vitro distribution of the enantiomers of the antimalarial drug halofantrine in human, dog and rat plasma lipoprotein-fractions.
  
  
  METHODS
  Plasma was spiked with racemic halofantrine (1,000 ng/ml) and incubated for 1 h at 37 degree C. The fractions (high and low density lipoproteins, triglyceride-rich lipoproteins and lipoprotein deficient plasma) were separated using density gradient ultracentrifugation. Fractions were assayed for halofantrine enantiomer using stereospecific high performance liquid chromatography.
  
  
  RESULTS
  The (-) enantiomer of halofantrine displayed higher affinity for the lipoprotein-deficient fraction than the (+) enantiomer in all three species. The (+) enantiomer was predominately located in the lipoprotein rich fractions 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 halofantrine distribution to the plasma fractions tested. There were substantial interspecies differences in the pattern of distribution of halofantrine enantiomers within the different fractions. A significant positive relationship was observed between halofantrine uptake into lipoprotein-rich fractions and the percent of apolar core lipid in those fractions. There was also a strong negative correlation between total protein concentration and the enantiomeric ratio in the lipoprotein-deficient plasma fraction.
  
  
  CONCLUSIONS
  Distribution of halofantrine enantiomer to plasma lipoprotein-fractions is stereoselective and species specific. This differential binding of halofantrine enantiomers to lipoproteins may need to be considered in viewing pharmacokinetic and pharmacodynamic data involving the drug.
authors.affiliation: Western University of Health Sciences, College of Pharmacy, Pomona, California 91766-1854, USA. dbrocks@westernu.edu
authors.forename: D R
authors.initials: DR
authors.lastname: Brocks
authors.forename: M
authors.initials: M
authors.lastname: Ramaswamy
authors.forename: A I
authors.initials: AI
authors.lastname: MacInnes
authors.forename: K M
authors.initials: KM
authors.lastname: Wasan
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000493:pharmacokinetics*; D004285:Dogs; D006801:Humans; D008074:Lipoproteins / Q000097:blood*; D010616:Phenanthrenes / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D013237:Stereoisomerism
chemical_list: D000962:Antimalarials; D008074:Lipoproteins; D010616:Phenanthrenes; C023768:halofantrine