title: Lack of effect of halofantrine on hepatic drug metabolism in the rat in vivo and in vitro.
abstract: The effect of the antimalarial drug halofantrine (Hf) on hepatic drug metabolism in the rat has been studied in vivo and in vitro using different model drug substrates. Hf in vitro produced no significant effect on the values of Km and Vmax for aminopyrine N-demethylation or 7-ethoxycoumarin O-dealkylation in microsomes incubated with Hf (0.01-0.1 mM) or on the rate of N-demethylation of aminopyrine or O-dealkylation of Ec in microsomes produced from rats dosed chronically with Hf (200 mg/kg) for 4 days. The disposition of antipyrine (Ap) was investigated in the isolated perfused rat liver preparation (IPRL). Following the administration of bolus doses of Hf (0.5, 2.5 and 5.0 mg) no significant changes were observed in the half-life (t1/2), clearance (Cl) or apparent volume of distribution (Vd) for Ap compared with controls. Pentobarbitone induced sleeping time was also assessed in mice. No significant difference was determined in time to recovery of the righting reflex for mice receiving Hf as single oral doses or chronically over 4 days when compared with appropriate controls. The potential for selective isoenzyme effects was studied in vivo. The three principal urinary metabolites of Ap, norantipyrine (Np), 3-OH and 4-OH Ap were measured in rat urine, with no significant change in urinary recovery of Ap or any of the metabolites in the presence of Hf (1.25 mg/kg i.p.) compared with controls. These results suggest that Hf is not, in contrast to many commonly used quinoline antimalarials, a potent or specific inhibitor of drug metabolism in vitro or in vivo.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Liverpool, U.K.
authors.forename: K A
authors.initials: KA
authors.lastname: Milton
authors.forename: P E
authors.initials: PE
authors.lastname: Hoaksey
authors.forename: S A
authors.initials: SA
authors.lastname: Ward
authors.forename: G
authors.initials: G
authors.lastname: Edwards
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D000983:Antipyrine / Q000493:pharmacokinetics / Q000652:urine; D001646:Bile / Q000032:analysis; D005260:Female; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010477:Perfusion; D010616:Phenanthrenes / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D000962:Antimalarials; D010616:Phenanthrenes; D006899:Mixed Function Oxygenases; C023768:halofantrine; D000983:Antipyrine