title: 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.
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 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.
authors.affiliation: Department of Forensic Pharmacology & Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Steuer
authors.affiliation: Department of Forensic Pharmacology & Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland.
authors.forename: Corina
authors.initials: C
authors.lastname: Schmidhauser
authors.affiliation: Department of Forensic Pharmacology & Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland.
authors.forename: Eva H
authors.initials: EH
authors.lastname: Tingelhoff
authors.affiliation: Psychopharmacology Research, Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Basel, Switzerland.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Schmid
authors.affiliation: Psychopharmacology Research, Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Basel, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Rickli
authors.affiliation: Department of Forensic Pharmacology & Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kraemer
authors.affiliation: Psychopharmacology Research, Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Basel, Switzerland.
authors.forename: Matthias E
authors.initials: ME
authors.lastname: Liechti
mesh_terms: D019540:Area Under Curve; D016642:Bupropion / Q000494:pharmacology; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000502:physiology*; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000494:pharmacology; D004311:Double-Blind Method; D006801:Humans; D008658:Inactivation, Metabolic / Q000187:drug effects; D053858:Metabolic Networks and Pathways; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000737:chemistry / Q000493:pharmacokinetics*; D010949:Plasma / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D016642:Bupropion; D019389:Cytochrome P-450 CYP2D6; D018817:N-Methyl-3,4-methylenedioxyamphetamine