Formation of two metyrapone N-oxides by rat liver microsomes
De Graeve, J.; Gielen, J.E.; Kahl, G.F.; Tüttenberg, K.H.; Kahl, R.; Maume, B.
Drug Metabolism and Disposition the Biological Fate of Chemicals 7(3): 166-170
1979
ISSN/ISBN: 0090-9556 PMID: 38088 Document Number: 139445
In the presence of phenobarbital-pretreated rat liver microsomes and under oxidative conditions, metyrapone is transformed in vitro into reduced metyrapone and two other metabolites. In an effort to further characterize those metabolites, large-scale incubations of metyrapone were performed. Untransformed substrate and metabolites were extracted into chloroform under alkaline conditions and separated by thin-layer chromatography. The nature of the metabolites as N-oxides located on either pyridine ring was established by physical methodologies, mainly electron-impact and chemical-ionization mass spectrometry, and also by chemical reactions with titanous chloride. The formation of both N-oxides was increased in microsomes from phenobarbital-, but not from 3-methylcholanthrene-pretreated animals. N-Oxide formation during metyrapone metabolism might be an important step in its inhibitory action on the cytochrome P-450-mediated drug metabolism.