Nitrofurazone: kinetics and oxidative stress in the singlepass isolated perfused rat liver.
The disposition of the antibiotic nitrofurazone was studied in the singlepass isolated perfused rat liver. Both the effects of the steady-state level of drug and the composition of the perfusate were evaluated. The higher level (120 micrograms/ml) of nitrofurazone in a perfusion medium lacking the glutathione (GSH) precursors, glycine, glutamic acid and cysteine, caused a marked increase in bile flow (from 1.01 +/- 0.07 to 2.33 +/- 1.07 microliters/min/g), massive biliary efflux of glutathione disulfide (GSSG) (from 0.55 +/- 0.07 to 60.6 +/- 25.4 nmol/min/g) and a sharp decline in the caval efflux of GSH (to undetectable levels) and the tissue level of GSH (from 5.74 +/- 0.20 to 2.68 +/- 0.13 mumol/g). Even after the drug was discontinued, these parameters were not restored to control levels. The lower level (30 micrograms/ml) of nitrofurazone with or without amino acid supplementation and the higher level with supplementation induced less dramatic effects. Using [35S]methionine, a new conjugated metabolite of nitrofurazone and glutathione was detected. The data suggest that the toxicity of the reactive oxygen species generated by the redox cycling of the nitro group and the reactive metabolites generated by further reduction of nitrofurazone can be mitigated by adequate glutathione levels, but that livers lacking sufficient glutathione to scavenge these reactive species may be damaged.
Hoener
B A
BA
Department of Pharmacy, School of Pharmacy, University of California, San Francisco 94143.
D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000378:metabolism; D009583:Nitrofurazone / Q000493:pharmacokinetics* / Q000494:pharmacology; D010084:Oxidation-Reduction; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains
D008715:Methionine; D005978:Glutathione; D009583:Nitrofurazone