Steuer, Andrea E. and Schmidhauser, Corina and Tingelhoff, Eva H. and Schmid, Yasmin and Rickli, Anna and Kraemer, Thomas and Liechti, Matthias E.. (2016) 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, 11 (3). e0150955.
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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.
Faculties and Departments: | 03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie 03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie 03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Psychopharmacology Research (Liechti) |
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UniBasel Contributors: | Liechti, Matthias Emanuel |
Item Type: | Article, refereed |
Article Subtype: | Research Article |
Publisher: | Public Library of Science |
e-ISSN: | 1932-6203 |
Note: | Publication type according to Uni Basel Research Database: Journal article |
Language: | English |
Identification Number: |
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edoc DOI: | |
Last Modified: | 31 Aug 2018 06:38 |
Deposited On: | 21 Mar 2016 13:22 |
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