Pharmacokinetics of halofantrine in the rat: Stereoselectivity and interspecies comparisons

The antimalarial drug, halofantrine, is chiral and is administered clinical ly as the racemate. In order to define the pharmacokinetic properties of ha lofantrine enantiomers in the rat, male Sprague-Dawley rats (264-311 g) wer e given halofantrine HCl orally (n = 5; 14 mg/kg) or intravenously (iv) (n = 5; 2 mg/kg). Plasma samples were collected over a 72 h period, and these were assayed for halofantrine enantiomer concentrations using a stereospeci fic reverse phase HPLC assay. After dosing by both routes of administration the (+) enantiomer was found to have significantly higher AUG, and higher C-max 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 admin istration was less than 27%. Urinary excretion was a negligible route of el imination of unchanged drug. Using allometry, the pharmacokinetics of (+/-) -halofantrine in rats scaled nicely with literature data from dogs and huma ns. The pharmacokinetic properties of halofantrine enantiomers in the rat r esembled those seen in humans, indicating that the rat is a good model for the study of halofantrine pharmacokinetics. Copyright (C) 1999 John Wiley & Sons, Ltd.