Pharmacokinetics of halofantrine in the rat: stereoselectivity and interspecies comparisons

The antimalarial drug, halofantrine, is chiral and is administered clinically as the racemate. In order to define the pharmacokinetic properties of halofantrine enantiomers in the rat, male Sprague-Dawley rats (264-311 g) were given halofantrine HCl orally (n = 5; 14 mg/kg) or intravenously (i.v.) (n = 5; 2 mg/kg). Plasma samples were collected over a 72 h period, and these were assayed for halofantrine enantiomer concentrations using a stereospecific reverse phase HPLC assay. After dosing by both routes of administration the (+) enantiomer was found to have significantly higher AUC, and higher Cmax after oral dosing. Pharmacokinetic analysis indicated that in the rat, the (+) enantiomer is cleared slower, and is less extensively distributed than its antipode. The bioavailability of the enantiomers after oral administration was less than 27%. Urinary excretion was a negligible route of elimination of unchanged drug. Using allometry, the pharmacokinetics of (+/-)-halofantrine in rats scaled nicely with literature data from dogs and humans. The pharmacokinetic properties of halofantrine enantiomers in the rat resembled those seen in humans, indicating that the rat is a good model for the study of halofantrine pharmacokinetics.