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

PloS One
Andrea E SteuerMatthias E Liechti

Abstract

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 ...Continue Reading

References

May 1, 1987·Pharmacology, Biochemistry, and Behavior·M D Schechter
Mar 1, 1988·Pharmacology, Biochemistry, and Behavior·R A GlennonG Patrick
Aug 1, 1997·Pharmacology, Biochemistry, and Behavior·L E Baker, M M Taylor
Jan 19, 1999·JAMA : the Journal of the American Medical Association·J R HughesS Shiffman
Feb 15, 2000·British Journal of Clinical Pharmacology·Rafael de la TorreJordi Camí
Mar 18, 2000·Toxicology Letters·Hans H MaurerFrank T Peters
Nov 21, 2000·Annals of the New York Academy of Sciences· de la Torre RJordi Camí
Sep 18, 2001·Chemical Research in Toxicology·Mireia SeguraRafael de la Torre
Jul 19, 2003·Pharmacological Reviews·A Richard GreenM Isabel Colado
Jul 2, 2004·Therapeutic Drug Monitoring·Rafael de la TorreJordi Camí
May 7, 2005·Journal of Clinical Psychopharmacology·Michael KotlyarDavid E Adson
Jul 26, 2005·European Journal of Clinical Pharmacology·Rafael de la TorreJordi Camí
Dec 22, 2005·Clinical Therapeutics·James W JeffersonKeith T Muir
Mar 3, 2006·Journal of Psychopharmacology·Neil Easton, Charles A Marsden
Jul 28, 2007·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Rebecka Coles, E D Kharasch
Apr 19, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Melinda J ReeseDonavon J McConn
Aug 30, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Markus R MeyerHans H Maurer
Nov 11, 2008·Current Drug Metabolism·Romuald Laine
Apr 18, 2009·Molecular Neurobiology·João Paulo CapelaFélix Carvalho
Jul 25, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Melanie MuellerGeorge A Ricaurte
Nov 12, 2009·Clinical Pharmacokinetics·Shu-Feng Zhou
Apr 15, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Irene Antolino-LoboMajorie B M van Duursen
Oct 14, 2010·Journal of Enzyme Inhibition and Medicinal Chemistry·Yuping LiuRenke Dai
Mar 7, 2012·Archives of Toxicology·Márcia CarvalhoMaria de Lourdes Bastos
Mar 15, 2013·Clinical Pharmacology and Therapeutics·J K HicksClinical Pharmacogenetics Implementation Consortium

Citations

Sep 7, 2017·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Ranjeet Prasad DashNuggehally R Srinivas
Nov 7, 2019·Journal of Clinical Psychopharmacology·Michael J MossToxicology Investigators Consortium (ToxIC)

Methods Mentioned

BETA
sulfotransferases
MDA

Clinical Trials Mentioned

NCT01771874

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