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

The main objective of this study was to determine the pharmacokinetics of t he 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 conc entrations 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 AUC(0-x) after oral and intravenous dosi ng were 3.7 and 2.8, respectively. After intravenous doses of DHF, the (-): (+) enantiomeric ratios of Cl and V-dss were approximately 2.8. There were no significant differences between the enantiomers in t(1/2) (Mean 14-23 h) or t(max) (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% o f the dose of HF is metabolized to DHF enantiomers. It was concluded that D HF possesses a pharmacokinetic profile similar to that of HF, each possessi ng low values of clearance and high volume of distribution. DHF differed fr om HF in its degree of stereoselectivity in pharmacokinetics, and in its ex tent of oral bioavailability. Copyright (C) 2000 John Wiley & Sons, Ltd.