CYTOCHROME-P-455 COMPLEX-FORMATION IN THE METABOLISM OF PHENYLALKYLAMINES .4. SPECTRAL EVIDENCES FOR METABOLIC CONVERSION OF METHAMPHETAMINE TO N-HYDROXYAMPHETAMINE

Incubation of liver microsomes from phenobarbital-treated rats with N-methylamphetamine (1) and its N-oxidized congeners N-hydroxy-N-methylamphetamine (2), N-methylene-1-phenyl-2-pro-pylamineN-oxide (3a) and N-(1-phenyl-2-propylidene)methylamine N-oxide (3b) gave rise to the formation of cytochrome P-450 product complexes characterized by maximum absorbances in the 453-457 nm region. Compounds 1, 2 and 3a showed maximum absorbances at 456 nm and for 2 and 3a both the rate and extent of complex formation was increased several fold over those of 1, with the complexing activity being about 90 per cent of that of N-hydroxyamphetamine (4a). Contrary to 1, 2, 3a and 4a, nitrone 3b showed its maximum absorbance at 453 nm and the spectral perturbations were identical to those seen with N-hydroxymethylamine (4b). Demethylation of 1 and 2, as monitored by formaldehyde production, showed good correlation with the complex formation. From the results it seems safe to conclude that 3a, formed after metabolic N-oxidation of N-methylamphetamine (1), undergoes further conversion to N-hydroxyamphetamine (4a), the latter being the ultimate precursor to the ligand forming the cytochrome P-455 complex. The results substantiate the notion that there is a preference for the formation of nitrones related to 3a rather than 3b during the metabolism of N-alkylamphetamines. Thus, in addition to α-carbon oxidation, N-oxidation is indicated as a route instrumental to the metabolic demethylation of N-methylamphetamine. © 1979.