Aerobic metabolism of niridazole by rat liver microsomes
Blumer, J.L.; Novak, R.F.; Lucas, S.V.; Simpson, J.M.; Webster, L.T.
Molecular Pharmacology 16(3): 1019-1030
1979
ISSN/ISBN: 0026-895X PMID: 119155 Document Number: 140814
The metabolism of the anthelmintic nitroheterocyclic compound niridazole by rat liver was studied under aerobic conditions in vitro. Metabolism was localized to the microsomal fraction. Four metabolites of niridazole were isolated from these microsomal systems by high pressure liquid chromatography. The metabolites were characterized by mass spectrometry and 1H Fourier transform NMR spectroscopy as the 4-hydroxy, 5-hydroxy, 4,5-dihydroxy and the 4,5-dehydro derivatives of the imidazolidinone ring; the nitrothiazole portion of niridazole apparently was unaltered. The aerobic metabolism required O2 and exogenous reducing equivalents (NADPH was more effective than NADH), and to be inhibited by CO, suggesting a cytochrome P-450 catalyzed reaction. Inducers of microsomal cytochrome P-450, phenobarbital and 3-methylcholanthrene, enhanced niridazole metabolism. Metabolite profiles varied quantitatively with different inducers. Experiments with individual aerobic metabolites showed precursor-product relationships that are consistent with formation of an epoxide intermediate in the overall metabolic sequence.