The reductive metabolism of metronidazole and ronidazole by aerobic liver microsomes.

Rat hepatic microsomal incubations supplemented with NADPH reduce metronidazole to its nitro anion radical. Under aerobic conditions, oxygen reacts with the anion radical to produce superoxide and to regenerate metronidazole. Superoxide production was followed by spin-trapping with DMPO, by the adrenochrome assay, and by the stimulation of oxygen consumption. Under anaerobic conditions, the anion radical is thought to be further reduced to a toxic intermediate. This metabolic cycle explains the reductive activation of metronidazole, and provides an explanation for the selective toxicity of metronidazole toward anaerobic infections and hypoxic tumor cells. Ronidazole follows the same metabolic pathway, so it is likely that all 5-nitroimidazoles will have an aerobic futile metabolism.