Involvement of CYP2D6 in the in vitro metabolism of amphetamine, two N-alkylamphetamines and their 4-methoxylated derivatives

1. Amphetamine (AM) and five amphetamine derivatives, N-ethylamphetamine (N EA), N-butylamphetamine (NBA), 4-methoxyamphetamine (RI-AM), 4-methoxy-N-et hylamphetamine (M-NEA) and 4-methoxy-N-butylamphetamine (M-NBA) were incuba ted with microsomal preparations from cells expressing human CYP2D6 to dete rmine whether the enzyme was capable of catalyzing the direct ring oxidatio n of all substrates; the N-dealkylation of NEA, NEA, M-NEA and M-NBA; and t he O-demethylation of M-AM, M-NEA and M-NBA. 2. None of the six compounds examined was N-dealkylated to any extent. 3. The only metabolites produced from,AM, NEA and NEA were the correspondin g ring 4-hydroxylated compounds, and the rates of formation were low. 4. All ring l-methoxylated substrates were efficiently O-demethylated by CY P2D6 to their corresponding phenols. The size of the N-alkyl group influenc ed the rates of formation of these phenolamines. In contrast to reported fi ndings with 2- and 3-methoxyamphetamines, none of the 4-methoxyamphetamines was ring-oxidized in the CYP2D6 enzyme system to 2- or 3-hydroxy-4-methoxy amphetamines or to dihydroxy-amphetamines.