PMID- 26967321
OWN - NLM
STAT- MEDLINE
DCOM- 20161213
LR  - 20190219
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 11
IP  - 3
DP  - 2016
TI  - Impact of Cytochrome P450 2D6 Function on the Chiral Blood Plasma 
      Pharmacokinetics of 3,4-Methylenedioxymethamphetamine (MDMA) and Its Phase I and 
      II Metabolites in Humans.
PG  - e0150955
LID - 10.1371/journal.pone.0150955 [doi]
LID - e0150955
AB  - 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) metabolism is known to be 
      stereoselective, with preference for S-stereoisomers. Its major metabolic step 
      involves CYP2D6-catalyzed demethylenation to 3,4-dihydroxymethamphetamine (DHMA), 
      followed by methylation and conjugation. Alterations in CYP2D6 genotype and/or 
      phenotype have been associated with higher toxicity. Therefore, the impact of 
      CYP2D6 function on the plasma pharmacokinetics of MDMA and its phase I and II 
      metabolites was tested by comparing extensive metabolizers (EMs), intermediate 
      metabolizers (IMs), and EMs that were pretreated with bupropion as a metabolic 
      inhibitor in a controlled MDMA administration study. Blood plasma samples were 
      collected from 16 healthy participants (13 EMs and three IMs) up to 24 h after 
      MDMA administration in a double-blind, placebo-controlled, four-period, 
      cross-over design, with subjects receiving 1 week placebo or bupropion 
      pretreatment followed by a single placebo or MDMA (125 mg) dose. Bupropion 
      pretreatment increased the maximum plasma concentration (Cmax) and area under the 
      plasma concentration-time curve from 0 to 24 h (AUC24) of R-MDMA (9% and 25%, 
      respectively) and S-MDMA (16% and 38%, respectively). Bupropion reduced the Cmax 
      and AUC24 of the CYP2D6-dependently formed metabolite stereoisomers of DHMA 
      3-sulfate, DHMA 4-sulfate, and 4-hydroxy-3-methoxymethamphetamine (HMMA sulfate 
      and HMMA glucuronide) by approximately 40%. The changes that were observed in IMs 
      were generally comparable to bupropion-pretreated EMs. Although changes in 
      stereoselectivity based on CYP2D6 activity were observed, these likely have low 
      clinical relevance. Bupropion and hydroxybupropion stereoisomer pharmacokinetics 
      were unaltered by MDMA co-administration. The present data might aid further 
      interpretations of toxicity based on CYP2D6-dependent MDMA metabolism.
FAU - Steuer, Andrea E
AU  - Steuer AE
AD  - Department of Forensic Pharmacology & Toxicology, Zurich Institute of Forensic 
      Medicine, University of Zurich, Zurich, Switzerland.
FAU - Schmidhauser, Corina
AU  - Schmidhauser C
AD  - Department of Forensic Pharmacology & Toxicology, Zurich Institute of Forensic 
      Medicine, University of Zurich, Zurich, Switzerland.
FAU - Tingelhoff, Eva H
AU  - Tingelhoff EH
AD  - Department of Forensic Pharmacology & Toxicology, Zurich Institute of Forensic 
      Medicine, University of Zurich, Zurich, Switzerland.
FAU - Schmid, Yasmin
AU  - Schmid Y
AD  - Psychopharmacology Research, Division of Clinical Pharmacology and Toxicology, 
      Department of Biomedicine and Department of Clinical Research, University 
      Hospital Basel, Basel, Switzerland.
FAU - Rickli, Anna
AU  - Rickli A
AD  - Psychopharmacology Research, Division of Clinical Pharmacology and Toxicology, 
      Department of Biomedicine and Department of Clinical Research, University 
      Hospital Basel, Basel, Switzerland.
FAU - Kraemer, Thomas
AU  - Kraemer T
AD  - Department of Forensic Pharmacology & Toxicology, Zurich Institute of Forensic 
      Medicine, University of Zurich, Zurich, Switzerland.
FAU - Liechti, Matthias E
AU  - Liechti ME
AD  - Psychopharmacology Research, Division of Clinical Pharmacology and Toxicology, 
      Department of Biomedicine and Department of Clinical Research, University 
      Hospital Basel, Basel, Switzerland.
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20160311
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Cytochrome P-450 CYP2D6 Inhibitors)
RN  - 01ZG3TPX31 (Bupropion)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2D6)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Area Under Curve
MH  - Bupropion/pharmacology
MH  - Cross-Over Studies
MH  - Cytochrome P-450 CYP2D6/genetics/*physiology
MH  - Cytochrome P-450 CYP2D6 Inhibitors/pharmacology
MH  - Double-Blind Method
MH  - Humans
MH  - Inactivation, Metabolic/drug effects
MH  - Metabolic Networks and Pathways
MH  - N-Methyl-3,4-methylenedioxyamphetamine/chemistry/*pharmacokinetics
MH  - Plasma/*metabolism
MH  - Stereoisomerism
PMC - PMC4788153
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2016/03/12 06:00
MHDA- 2016/12/15 06:00
PMCR- 2016/03/11
CRDT- 2016/03/12 06:00
PHST- 2015/11/19 00:00 [received]
PHST- 2016/02/22 00:00 [accepted]
PHST- 2016/03/12 06:00 [entrez]
PHST- 2016/03/12 06:00 [pubmed]
PHST- 2016/12/15 06:00 [medline]
PHST- 2016/03/11 00:00 [pmc-release]
AID - PONE-D-15-50475 [pii]
AID - 10.1371/journal.pone.0150955 [doi]
PST - epublish
SO  - PLoS One. 2016 Mar 11;11(3):e0150955. doi: 10.1371/journal.pone.0150955. 
      eCollection 2016.