Molecular Pharmacology, Vol 16, 1019-1030, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

Aerobic Metabolism of Niridazole by Rat Liver Microsomes

¹ Department of Pharmacology, Northwestern University Medical School, Chicago, Illinois 60611 and the Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

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 nuclear magnetic resonance 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 was shown to require 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, were found to enhance 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.