OXIDATION OF METHAMPHETAMINE AND METHYLENEDIOXYMETHAMPHETAMINE BY CYP2D6

Methamphetamine (MeAmp) abuse has recently experienced a re-surgence and approaches to the treatment of its addiction similar to those used with cocaine have been considered. As the treat-ment regimes are likely to use drugs whose metabolism is related to that of MeAmp, studies were initiated to establish the enzymol-ogy of the fate of MeAmp. This report describes investigations of the role of CYP2D6, the human isoform of the enzyme that catalyzes debrisoquine hy-droxylation, in the 4-hydroxylation and N-demethylation of MeAmp. The results of studies with human liver microsomes including those from a genetically poor metabolizer with respect to CYP2D6, showing correlation between MeAmp and metoprolol hydroxyla-tion and MDMA demethylenation, were consistent with a major involvement of CYP2D6 in the aromatic 4-hydroxylation of MeAmp. This was confirmed by studies with recombinant CYP2D6 ex