PMID- 9264312
OWN - NLM
STAT- MEDLINE
DCOM- 19970908
LR  - 20190623
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 53
IP  - 11
DP  - 1997 Jun 1
TI  - Interactions of amphetamine analogs with human liver CYP2D6.
PG  - 1605-12
AB  - The interaction of fifteen amphetamine analogs with the genetically polymorphic 
      enzyme CYP2D6 was examined. All fourteen phenylisopropylamines tested were 
      competitive inhibitors of CYP2D6 in human liver microsomes. The presence of a 
      methylenedioxy group in the 3,4-positions of both amphetamine (Ki = 26.5 microM) 
      and methamphetamine (Ki = 25 microM) increased the affinity for CYP2D6 to 1.8 and 
      0.6 microM, respectively. Addition of a methoxy group to amphetamine in the 
      2-position also increased the affinity for CYP2D6 (Ki = 11.5 microM). The 
      compound with the highest affinity for CYP2D6 was an amphetamine analog (MMDA-2) 
      having both a methoxy group in the 2-position and a methylenedioxy group (Ki = 
      0.17 microM). Mescaline did not interact with CYP2D6. O-Demethylation of 
      p-methoxyamphetamine (PMA) by CYP2D6 was characterized (Km = 59.2 +/- 22.4 
      microM, and Vmax = 29.3 +/- 16.6 nmol/mg/hr, N = 6 livers). This reaction was 
      negligible in CYP2D6-deficient liver microsomes, was inhibited stereoselectively 
      by the quinidine/quinine enantiomer pair, and was cosegregated with 
      dextromethorphan O-demethylation (r = 0.975). The inhibitory effect of 
      methylenedioxymethamphetamine (MDMA) was enhanced by preincubation with 
      microsomes, suggesting that MDMA may produce a metabolite complex with CYP2D6. 
      These findings suggest that phenylisopropylamines as a class interact with CYP2D6 
      as substrates and/or inhibitors. Their use may cause metabolic interactions with 
      other drugs that are CYP2D6 substrates, and the potential for polymorphic 
      oxidation via CYP2D6 may be a source of interindividual variation in their abuse 
      liability and toxicity.
FAU - Wu, D
AU  - Wu D
AD  - Addiction Research Foundation and Department of Pharmacology, University of 
      Toronto, Canada.
FAU - Otton, S V
AU  - Otton SV
FAU - Inaba, T
AU  - Inaba T
FAU - Kalow, W
AU  - Kalow W
FAU - Sellers, E M
AU  - Sellers EM
LA  - eng
PT  - Journal Article
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Amphetamines)
RN  - 0 (Cytochrome P-450 CYP2D6 Inhibitors)
RN  - 15402-84-3 (N-desmethylmethoxyphenamine)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - OVB8F8P39Q (4-methoxyamphetamine)
SB  - IM
MH  - Amphetamines/chemistry/metabolism/*pharmacology
MH  - Binding, Competitive
MH  - *Cytochrome P-450 CYP2D6 Inhibitors
MH  - Humans
MH  - Microsomes, Liver/*enzymology
MH  - N-Methyl-3,4-methylenedioxyamphetamine/pharmacology
MH  - Substrate Specificity
EDAT- 1997/06/01 00:00
MHDA- 1997/06/01 00:01
CRDT- 1997/06/01 00:00
PHST- 1997/06/01 00:00 [pubmed]
PHST- 1997/06/01 00:01 [medline]
PHST- 1997/06/01 00:00 [entrez]
AID - S0006-2952(97)00014-2 [pii]
AID - 10.1016/s0006-2952(97)00014-2 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 1997 Jun 1;53(11):1605-12. doi: 10.1016/s0006-2952(97)00014-2.