Ketoconazole, a cytochrome P450 inhibitor can potentiate the antimalarial action of α/β arteether against MDR Plasmodium yoelii nigeriensis

Abstract

The emergence of multidrug resistant (MDR) strains of Plasmodium falciparum in South East Asia and other tropical countries, is posing serious challenge for the international efforts to eradicate malaria. New drug target/ACT/non-ACT combinations need to be discovered to control the spread of MDR malaria. The present communication deals with antimalarial potential of a new combination comprising of ketoconazole (KTZ) (an antifungal/inhibitor of CYP3A4) and artemisinin derivative α/β arteether (ART). In vitro interactions of these drugs against chloroquine sensitive/resistant P. falciparum (Pf3D7/K1) have shown an overall additive interaction with mean sum fractional inhibitory concentrations (∑FICs) of 1.1±0.33 against 3D7 and 1.51±0.42 against K1 strains.Sub-curative doses of KTZ (150mg/kg×7 days) combined with ART (6.25–12.5mg/kg×5 days) both administered orally have shown 100% curative action against MDR P. yoelii nigeriensis in Swiss mice. Besides lower dose of KTZ (75mg/kg) which is non-curative itself, in combination with 12.5mg/kg×5 days of ART treatment, was also 100% curative. Further studies on mechanism of action of KTZ (150mg/kg single dose) have shown that significant inhibitory action of the antifungal drug is through very high level of suppression of CYP (nearly 90%) compared to that of healthy mice liver. The companion drug therapy comprising of KTZ together with ART (25mg/kg×1 dose) also produced more than 50% inhibitory effect on the CYP enzyme level. Since the ART is known to be rapidly metabolized by the liver cytochrome P450 (CYP) 3A4 to Dihydroquinghasu, the combined therapy with KTZ (a strong CYP 3A4 inhibitor) may influence the pharmacokinetics of ART and consequently slow down the drug metabolism and prolong the plasma life of the active drug, which would contribute to enhanced antimalarial action of ART against MDR P. yoelii nigeriensis.