Disposition of Nifurtimox and Metabolite Activity Against Trypanosoma cruzi using Rat Isolated Perfused Liver

Abstract

Abstract— Nifurtimox disposition was investigated using the rat isolated perfused‐liver method after administration of 25 μg mL−1 nifurtimox, and its disappearance was monitored by analysing the perfusate sample at various times. Biliary excretion was also measured. The drug concentration profile underwent a biexponential decline over the 2‐h study period, with a terminal half‐life of 62·76 ± 17·56 min. Nifurtimox is a high clearance compound (15·23±5·53 mL min−1). The extraction ratio was 0·621 ±0·159. Biliary excretion accounted for 0·05% of the dose, the remainder consisting of highly polar metabolites. By 2 h, a minimal fraction of unchanged nifurtimox was recovered from the perfusate. Nifurtimox activity against Trypanosoma cruzi (clone CA‐1) during the perfusion was also determined. Epimastigotes isolated from continuous culture were exposed to the samples of perfusate at different perfusion times in a microtitre plate. After an incubation time of 72 h at 27°C, the parasite numbe