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 (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.
Bach
M V
MV
Neurochemical Research Unit, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Coutts
R T
RT
Baker
G B
GB
D000661:Amphetamine / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D000662:Amphetamines / Q000378:metabolism / Q000493:pharmacokinetics; D002384:Catalysis; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D003913:Dextroamphetamine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D006900:Hydroxylation; D008658:Inactivation, Metabolic; D007700:Kinetics; D008861:Microsomes / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship
C121523:4-methoxy-N-butylamphetamine; C121522:4-methoxy-N-ethylamphetamine; D000662:Amphetamines; C016434:ethylamphetamine; C029114:d-N-butylamphetamine; D009249:NADP; D000661:Amphetamine; D019389:Cytochrome P-450 CYP2D6; C100230:4-methoxyamphetamine; D003913:Dextroamphetamine