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Contribution of Cytochrome P450 2D6 to 3,4-Methylenedioxymethamphetamine Disposition in Humans

Use of Paroxetine as a Metabolic Inhibitor Probe

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Abstract

Background: 3,4-Methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine derivative typically used for recreational purposes. The participation of cytochrome P450 (CYP) 2D6 in the oxidative metabolism of MDMA may suggest an increased risk of acute toxicity in CYP2D6 poor metabolisers. This study was aimed at assessing the contribution of CYP2D6 to MDMA disposition in vivo using paroxetine as a metabolic probe inhibitor. Paroxetine, a CYP2D6 inhibitor, was repeatedly administered before MDMA administration.

Study design: This was a randomised, double-blind, crossover, placebo-controlled trial conducted in seven healthy male volunteers who were CYP2D6 extensive metabolisers. Treatment conditions (paroxetine/MDMA and placebo/ MDMA) were randomly assigned. Each volunteer participated in two 3-day sessions. On days 1, 2 and 3 subjects received a single oral dose of paroxetine or placebo 20mg. On the third day, a single oral dose of MDMA 100mg was administered in both paroxetine and placebo conditions.

Methods: Plasma concentration-time profiles and urinary recoveries of MDMA and its metabolites were measured, as well as plasma concentrations of paroxetine, (3S,4R)-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-piperidine, and (3S,4R)-4-(4-fluorophenyl)-3-(3-methoxy-4-hydroxyphenoxymethyl)-piperidine (HM-paroxetine).

Results: Paroxetine given before MDMA resulted in significant increases of MDMA area under the plasma concentration-time curve from 0 to 27 hours (AUC27) [23%], AUC from zero to infinity (AUC∞) [27%] and maximum plasma concentration (Cmax) [17%], without significant differences in MDMA time to reach Cmax (tmax). MDMA elimination-related pharmacokinetic parameters showed a significant reduction of MDMA elimination rate constant (Ke) [−14%] and plasmatic clearance (CLP) [−29%]. In the case of 3,4-dihydroxymethamphetamine (HHMA), a 21% decrease in Cmax with no significant differences in AUC27, AUC∞, Ke and elimination half-life) were found. 4-Hydroxy-3-methoxymethamphetamine (HMMA) showed a decrease in plasma concentrations with a reduction in AUC27 (−28%), AUC∞ (−20%) and Cmax (−46%). In the case of 3,4-methylenedioxyamphetamine (MDA) an increase in Cmax (17%) and AUC27 (16%) was found. Following paroxetine pretreatment, the urinary recovery (0–45 hours) of MDMA increased by 11%; HHMA and HMMA urinary recoveries were 27% and 16% lower, respectively compared with placebo. The ratio of Cmax values of paroxetine and its metabolite on days 1 and 3 showed a 3-fold reduction, with no differences in tmax.

Discussion and conclusion: The contribution of CYP2D6 to MDMA metabolism in humans is not >30%, therefore other CYP isoenzymes may contribute to O-demethylenation of MDMA. Accordingly, the relevance of genetic polymorphism in CYP2D6 activity on MDMA effects and MDMA-induced acute toxicity should be examined as well as the interactions of other CYP2D6 substrates with MDMA, once the enzyme is inhibited. The pharmacokinetics of HM-paroxetine in humans after the administration of repeated doses is reported for the first time in this study.

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  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgements

This study was supported by Fondo de Investigación Sanitaria, Madrid, Spain (grants FIS 97/1198, FIS 98/0181, FIS 00/0777 and FIS 01/1336), ‘Area Progetto Droga’, Istituto Superiore di Sanità, Rome, Italy, and Generalitat de Catalunya, Barcelona, Spain (GENCAT-CIRIT; grant 2001SGR00407).

The authors thank Marta Pulido, MD, for editing the manuscript and for editorial assistance.

The authors have no conflicts of interest directly relevant to the content of this study.

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Authors and Affiliations

  1. Pharmacology Research Unit, Barcelona, Spain

    Mireia Segura, Magí Farré, Ana M. Peiró, Pere N. Roset, Ariel Ramírez, Jordi Ortuño, Jordi Segura &  Rafael de la Torre

  2. Universitat Pompeu Fabra, Barcelona, Spain

    Mireia Segura, Jordi Segura &  Rafael de la Torre

  3. Universitat Autònoma de Barcelona, Barcelona, Spain

    Magí Farré & Pere N. Roset

  4. Istituto Superiore di Sanità, Rome, Italy

    Simona Pichini, Roberta Pacifici & Piergiorgio Zuccaro

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  1. Mireia Segura
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Segura, M., Farré, M., Pichini, S. et al. Contribution of Cytochrome P450 2D6 to 3,4-Methylenedioxymethamphetamine Disposition in Humans. Clin Pharmacokinet 44, 649–660 (2005). https://doi.org/10.2165/00003088-200544060-00006

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