OXIDATION OF METHAMPHETAMINE AND METHYLENEDIOXYMETHAMPHETAMINE BY CYP2D6

Methamphetamine (MeAmp) abuse has recently experienced a resurgence an d approaches to the treatment of its addiction similar to those used w ith cocaine have been considered, As the treatment regimes are likely to use drugs whose metabolism is related to that of MeAmp, studies wer e initiated to establish the enzymology of the fate of MeAmp, This rep ort describes investigations of the role of CYP2D6, the human isoform of the enzyme that catalyzes debrisoquine hydroxylation, in the 4-hydr oxylation and N-demethylation of MeAmp, The results of studies with hu man liver microsomes including those from a genetically poor metaboliz er with respect to CYP2D6, showing correlation between MeAmp and metop rolol hydroxylation and MDMA demethylenation, were consistent with a m ajor involvement of CYP2D6 in the aromatic 4-hydroxylation of MeAmp. T his was confirmed by studies with recombinant CYP2D6 expressed in yeas t, which was also shown to effect the N-demethylation of MeAmp. The ra te of the 4-hydroxylation reaction was substantially slower than the d emethylenation of MDMA. In contrast to MeAmp, MDMA was not N-demethyla ted by CYP2D6, Since CYP2D6 participates in the major steps of MeAmp m etabolism, pharmacokinetic interactions are likely with other drug sub strates proposed for the treatment of MeAmp addiction, Furthermore, th e genetic polymorphism associated with the enzyme could manifest itsel f in abnormal responses to MeAmp.