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

Xenobiotica. 1999 Jul;29(7):719-32. doi: 10.1080/004982599238344.


1. Amphetamine (AM) and five amphetamine derivatives, N-ethylamphetamine (NEA), N-butylamphetamine (NBA), 4-methoxyamphetamine (M-AM), 4-methoxy-N-ethylamphetamine (M-NEA) and 4-methoxy-N-butylamphetamine (M-NBA) were incubated with microsomal preparations from cells expressing human CYP2D6 to determine whether the enzyme was capable of catalyzing the direct ring oxidation of all substrates; the N-dealkylation of NEA, NBA, M-NEA and M-NBA; and the 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 NBA were the corresponding ring 4-hydroxylated compounds, and the rates of formation were low. 4. All ring 4-methoxylated substrates were efficiently O-demethylated by CYP2D6 to their corresponding phenols. The size of the N-alkyl group influenced the rates of formation of these phenolamines. In contrast to reported findings with 2- and 3-methoxyamphetamines, none of the 4-methoxyamphetamines was ring-oxidized in the CYP2D6 enzyme system to 2- or 3-hydroxy-4-methoxyamphetamines or to dihydroxyamphetamines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphetamine / chemistry
  • Amphetamine / metabolism*
  • Amphetamine / pharmacokinetics
  • Amphetamines / metabolism
  • Amphetamines / pharmacokinetics
  • Catalysis
  • Cytochrome P-450 CYP2D6 / metabolism*
  • Dextroamphetamine / analogs & derivatives
  • Dextroamphetamine / metabolism
  • Dextroamphetamine / pharmacokinetics
  • Humans
  • Hydroxylation
  • Inactivation, Metabolic
  • Kinetics
  • Microsomes / metabolism
  • NADP / metabolism
  • Oxidation-Reduction
  • Structure-Activity Relationship


  • 4-methoxy-N-butylamphetamine
  • 4-methoxy-N-ethylamphetamine
  • Amphetamines
  • ethylamphetamine
  • d-N-butylamphetamine
  • NADP
  • Amphetamine
  • Cytochrome P-450 CYP2D6
  • 4-methoxyamphetamine
  • Dextroamphetamine