DISPOSITION OF NIFURTIMOX AND METABOLITE ACTIVITY AGAINST TRYPANOSOMA-CRUZI USING RAT ISOLATED-PERFUSED LIVER

Nifurtimox disposition was investigated using the rat isolated perfuse d-liver method after administration of 25 mug mL-1 nifurtimox, and its disappearance was monitored by analysing the perfusate sample at vari ous 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 wa s 0.621 +/- 0.159. Biliary excretion accounted for 0.05% of the dose, the remainder consisting of highly polar metabolites. By 2 h, a minima l fraction of unchanged nifurtimox was recovered from the perfusate. N ifurtimox activity against Trypanosoma cruzi (clone CA-1) during the p erfusion was also determined. Epimastigotes isolated from continuous c ulture were exposed to the samples of perfusate at different perfusion times in a microtitre plate. After an incubation time of 72 h at 27-d egrees-C, the parasite number in each well was counted under a microsc ope. From 0 to 75 min after the perfusion, the anti-trypanosomal activ ity decreased, but an increase in activity was observed at the later t imes. These findings show that active metabolites are formed during th e perfusion.