Stereoselective pharmacokinetics of desbutylhalofantrine, a metabolite of halofantrine, in the rat after administration of the racemic metabolite or parent drug

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Abstract
The main objective of this study was to determine the pharmacokinetics of the enantiomers of desbutylhalofantrine (DHF), a metabolite of halofantrine (HF), in the rat. Rats received either intravenous (2 mg/kg) or oral (7 mg/kg) (±)‐DHF HCl, or (±)‐HF HCl intravenously (3 mg/kg). Enantiomer concentrations in plasma were determined by a stereospecific assay. In all rats, the plasma concentrations of (+)‐DHF exceeded those of (−)‐DHF. After (±)‐DHF, the mean (+):(−) ratios of AUC0–∞ after oral and intravenous dosing were 3.7 and 2.8, respectively. After intravenous doses of DHF, the (−):(+) enantiomeric ratios of Cl and Vdss were approximately 2.8. There were no significant differences between the enantiomers in t1/2 (mean 14–23 h) or tmax (mean 10–12 h) after intravenous or oral administration of DHF. Oral bioavailability estimates of DHF enantiomers (>59%) were higher than those previously estimated for HF in the rat. The stereoselectivity in HF kinetics was not as pronounced as for DHF. It was estimated that over 44% of the dose of HF is metabolized to DHF enantiomers. It was concluded that DHF possesses a pharmacokinetic profile similar to that of HF, each possessing low values of clearance and high volume of distribution. DHF differed from HF in its degree of stereoselectivity in pharmacokinetics, and in its extent of oral bioavailability. Copyright © 2000 John Wiley & Sons, Ltd.