title: Mefloquine effect on disposition of halofantrine in the isolated perfused rat liver.
abstract: Halofantrine and mefloquine are antimalarial drugs used in the treatment of malaria, including that caused by chloroquine-resistant Plasmodium falciparum. Reports of drug-associated adverse reactions, including sudden death in one patient, have prompted concerns over the safety of halofantrine and the potential for drug-drug interactions. We used the isolated perfused rat liver (IPRL) model to investigate a possible hepatic metabolic or pharmacokinetic drug-drug interaction between halofantrine and mefloquine. Pharmacokinetic parameter estimates for halofantrine in the IPRL reflected the pattern seen in in-vivo studies with doses comparable with clinical doses. Halofantrine parameter estimates (mean +/- s.d.) were: volume of distribution (Vd), 7.53 +/- 1.45 mL (g liver)-1; clearance (CL), 0.11 +/- 0.07 mL min-1 (g liver)-1; initial distribution half-life (initial t1/2), 14.62 +/- 2.38 min; terminal half-life (terminal t1/2), 138.7 +/- 178.8 min; AUC 606 +/- 194 mg mL-1 min-1 (g liver)-1; elimination rate constant (Ke), 0.0135 +/- 0.012 min-1. Prior dosing with mefloquine did not affect halofantrine perfusate pharmacokinetic parameter estimates of Vd, Ke, initial and terminal t1/2 (P > 0.05). A single dose, short term (4-6 h) interaction showed significant changes in the perfusate clearance of halofantrine in mefloquine-pretreated livers using higher doses of halofantrine. Substantial changes were seen in bile production (P < 0.05) and biliary clearance (P < 0.05) of halofantrine in mefloquine-pretreated livers. These findings may have clinical implications in models utilizing multiple drug dosages or in patients with severe malaria who have disease-related cholestasis.
authors.affiliation: Walter Reed Army Institute of Research, Division of Experimental Therapeutics Washington, DC 20307-5100, USA.
authors.forename: K U
authors.initials: KU
authors.lastname: Leo
authors.forename: D L
authors.initials: DL
authors.lastname: Wesche
authors.forename: M T
authors.initials: MT
authors.lastname: Marino
authors.forename: T G
authors.initials: TG
authors.lastname: Brewer
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000378:metabolism / Q000494:pharmacology*; D019540:Area Under Curve; D004347:Drug Interactions; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D015767:Mefloquine / Q000494:pharmacology*; D008657:Metabolic Clearance Rate; D010477:Perfusion; D010616:Phenanthrenes / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000962:Antimalarials; D010616:Phenanthrenes; C023768:halofantrine; D015767:Mefloquine