Mefloquine Effect on Disposition of Halofantrine in the Isolated Perfused Rat Liver

Abstract

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 mefioquine-pretreated livers using higher doses of halofantrine. Substantial changes were seen in bile production (P < 005) and biliary clearance (P < 005) of halofantrine in mefioquine-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.