Subject(s)
Estranes/pharmacology , Microsomes, Liver/metabolism , Pharmaceutical Preparations/metabolism , Progestins/pharmacology , Aerobiosis , Allyl Compounds/pharmacology , Aniline Compounds/antagonists & inhibitors , Aniline Compounds/metabolism , Animals , Anisoles/antagonists & inhibitors , Anisoles/metabolism , Dealkylation , Hydroxylation , Hydroxysteroids/pharmacology , In Vitro Techniques , Kinetics , Lynestrenol/pharmacology , Male , Microsomes, Liver/drug effects , Nitro Compounds/antagonists & inhibitors , Nitro Compounds/metabolism , Norethindrone/pharmacology , Norgestrel/pharmacology , Oxidation-Reduction , Phenobarbital/pharmacology , Rats , SpectrophotometryABSTRACT
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.