PMID- 15328252
OWN - NLM
STAT- MEDLINE
DCOM- 20050201
LR  - 20141120
IS  - 0090-9556 (Print)
IS  - 0090-9556 (Linking)
VI  - 32
IP  - 11
DP  - 2004 Nov
TI  - Mechanism-based inactivation of CYP2D6 by methylenedioxymethamphetamine.
PG  - 1213-7
AB  - The potency of methylenedioxymethamphetamine (MDMA) as a mechanism-based 
      inhibitor of CYP2D6 has been defined using microsomes prepared from yeast 
      expressing the enzyme and from three human livers. The inhibitory effect was 
      increased by preincubation through formation of a metabolic intermediate complex. 
      Inactivation parameters (kinact and KI), defined with respect to the 
      O-demethylation of dextromethorphan, were 0.29 +/- 0.03 (S.E.) min(-1) and 12.9 
      +/- 3.6 (S.E.) microM for yeast-expressed CYP2D6, and 0.26 +/- 0.02 min(-1) and 
      14.4 +/- 2.5 microM, 0.15 +/- 0.01 min(-1) and 8.8 +/- 2.6 microM, and 0.12 +/- 
      0.05 min(-1) and 45.3 +/- 32.1 microM for the liver microsomal preparations. The 
      rate of inactivation of CYP2D6 by MDMA decreased when quinidine, a competitive 
      inhibitor of CYP2D6, was added to the primary incubation mixture. However, 
      inactivation was unaffected by the addition of glutathione. The results indicate 
      that MDMA is a potent mechanism-based inhibitor of CYP2D6, with implications for 
      understanding its in vivo disposition and drug interaction potential.
CI  - Copyright 2004 The American Society for Pharmacology and Experimental 
      Therapeutics
FAU - Heydari, A
AU  - Heydari A
AD  - Division of Clinical Sciences (South), University of Sheffield, UK.
FAU - Yeo, K Rowland
AU  - Yeo KR
FAU - Lennard, M S
AU  - Lennard MS
FAU - Ellis, S W
AU  - Ellis SW
FAU - Tucker, G T
AU  - Tucker GT
FAU - Rostami-Hodjegan, A
AU  - Rostami-Hodjegan A
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20040824
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Cytochrome P-450 CYP2D6 Inhibitors)
RN  - 0 (Enzyme Inhibitors)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2D6)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Cytochrome P-450 CYP2D6/*metabolism
MH  - *Cytochrome P-450 CYP2D6 Inhibitors
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Inhibitors/*pharmacology
MH  - Humans
MH  - Microsomes, Liver/drug effects/enzymology
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*pharmacology
EDAT- 2004/08/26 05:00
MHDA- 2005/02/03 09:00
CRDT- 2004/08/26 05:00
PHST- 2004/08/26 05:00 [pubmed]
PHST- 2005/02/03 09:00 [medline]
PHST- 2004/08/26 05:00 [entrez]
AID - dmd.104.001180 [pii]
AID - 10.1124/dmd.104.001180 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2004 Nov;32(11):1213-7. doi: 10.1124/dmd.104.001180. Epub 2004 
      Aug 24.