title: Disposition of nifurtimox and metabolite activity against Trypanosoma cruzi using rat isolated perfused liver.
abstract: Nifurtimox disposition was investigated using the rat isolated perfused-liver method after administration of 25 micrograms 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 degrees C, the parasite number in each well was counted under a microscope. From 0 to 75 min after the perfusion, the anti-trypanosomal activity decreased, but an increase in activity was observed at the later times. These findings show that active metabolites are formed during the perfusion.
authors.affiliation: Department of Pharmacy, Faculty of Chemistry, Pontifical Catholic University of Chile, Santiago.
authors.forename: G
authors.initials: G
authors.lastname: González-Martin
authors.forename: C
authors.initials: C
authors.lastname: Paulos
authors.forename: A
authors.initials: A
authors.lastname: Guevara
authors.forename: G
authors.initials: G
authors.lastname: Ponce
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009547:Nifurtimox / Q000493:pharmacokinetics* / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D009547:Nifurtimox