A new metabolite of methamphetamine; evidence for formation of N-[(1-methyl-2-phenyl)ethyl]ethanimine N-oxide.

1. N-Hydroxyamphetamine and N-hydroxymethamphetamine, metabolic intermediates of amphetamine and methamphetamine, showed no reactivity towards endogeneous protein, amino acids, nucleic acids and fatty acids. In contrast, formaldehyde, acetaldehyde and propionaldehyde reacted well with N-hydroxyamphetamine and slightly with N-hydroxymethamphetamine under mild conditions (pH 7.4, 37 degrees C). 2. Two products were isolated from the reaction mixture of acetaldehyde and N-hydroxyamphetamine. These were characterized as N-[(1-methyl-2-phenyl)ethyl]ethanimine N-oxide and N-[(1-methyl-2-phenyl)ethyl]butenimine N-oxide by mass and n.m.r. spectrometries. 3. N-[(1-Methyl-2-phenyl)ethyl]ethanimine N-oxide was formed by incubating methamphetamine with liver 9000 g supernatants of rats and guinea-pigs. The butenimine N-oxide derivative, however, could not be detected as a metabolite of methamphetamine in vitro. 4. N-[(1-Methyl-2-phenyl)ethyl]ethanimine N-oxide was also detected as a urinary metabolite of methamphetamine in rats and guinea-pigs. Thus, the ethanimine N-oxide was established as a novel metabolite of methamphetamine.