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Drug Metabolism and Personalized Therapy

Official journal of the European Society of Pharmacogenomics and Personalised Therapy

Editor-in-Chief: Llerena, Adrián

Editorial Board: Benjeddou, Mongi / Chen, Bing / Dahl, Marja-Liisa / Devinsky, Ferdinand / Hirata, Rosario / Hubacek, Jaroslav A. / Ingelman-Sundberg, Magnus / Maitland-van der Zee, Anke-Hilse / Manolopoulos, Vangelis G. / Marc, Janja / Melichar, Bohuslav / Meyer, Urs A. / Nair, Sujit / Nofziger, Charity / Peiro, Ana / Sadee, Wolfgang / Salazar, Luis A. / Simmaco, Maurizio / Turpeinen, Miia / Schaik, Ron / Shin, Jae-Gook / Visvikis-Siest, Sophie / Zanger, Ulrich M.

CiteScore 2018: 1.01

SCImago Journal Rank (SJR) 2018: 0.277
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Volume 32, Issue 3


Evaluation of the Ecstasy influence on tramadol and its main metabolite plasma concentration in rats

Bardia Jamali
  • Faculty of Pharmacy, Department of Pharmaceutics, Biopharmaceutics and Pharmacokinetics Division, Tehran University of Medical Sciences, Tehran, Iran
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/ Behjat Sheikholeslami / Yalda Hosseinzadeh Ardakani
  • Faculty of Pharmacy, Department of Pharmaceutics, Biopharmaceutics and Pharmacokinetics Division, Tehran University of Medical Sciences, Tehran, Iran
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/ Hoda Lavasani
  • Faculty of Pharmacy, Department of Pharmaceutics, Biopharmaceutics and Pharmacokinetics Division, Tehran University of Medical Sciences, Tehran, Iran
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/ Mohammad-Reza Rouini
  • Corresponding author
  • Faculty of Pharmacy, Department of Pharmaceutics, Biopharmaceutics and Pharmacokinetics Division, Tehran University of Medical Sciences, Tehran 14155-6451, Iran
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Published Online: 2017-09-16 | DOI: https://doi.org/10.1515/dmpt-2017-0018



Tramadol is prone to be abused alone, or in combination with 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy). It was reported that 95% of people with a history of substance abuse in the United States used tramadol in 2004. According to the WHO report in 2016, there was a growing number of tramadol abusers alone or in combination with psychoactive substances such as MDMA in particular in some Middle East countries. Higher concentrations of tramadol in plasma may lead to adverse drug reactions or lethal intoxication. In this study, the effect of MDMA on the pharmacokinetics of tramadol was examined in male rats.


The effect of MDMA on Tmax, Cmax, area under the curve, elimination rate, and half-life of tramadol and its metabolites was examined. Two control and two treatment groups were designed. The treatment groups received MDMA 18 h before the administration of tramadol. Jugular vein blood samples were analyzed by high-performance liquid chromatography with fluorescent detector to determine the concentrations of tramadol and its metabolites. Independent-sample t-test was used to define the differences between pharmacokinetic parameters of control and treatment groups.


When tramadol administered intraperitoneally, the absorption rate of this drug was reduced, and a lower Cmax (40%) with longer Tmax (eight-fold) was achieved. MDMA exerted greater inhibitory effects on cytochrome P450 3A4 (CYP3A4) than on cytochrome P450 2D6 (CYP2D6). The M2 metabolite ratio was reduced by half, and because of the inhibition of M2 production, the M1 plasma concentration slightly increased.


According to the obtained data, MDMA treatment affected the absorption, distribution and metabolism phases of tramadol. This treatment increased the concentration of tramadol if administered intravenously and can latent the absorption of tramadol in oral route. However, MDMA was introduced as CYP2D6 inhibitor; in this study, MDMA inhibited CYP3A4 isoenzymes as well. This finding is important for the compounds that are metabolized through CYP3A4. It can be proposed that in abusers of MDMA who only receive tramadol for medical or nonmedical purposes in short intervals, the dangers of the intravenous administration of tramadol should be considered, and if tramadol is administered orally, the desired effect may not be achieved at the routine dose.

Keywords: CYP3A4; drug-drug interaction; Ecstasy; MDMA abusers; pharmacokinetic; tramadol


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About the article

Received: 2017-05-27

Accepted: 2017-08-09

Published Online: 2017-09-16

Published in Print: 2017-09-26

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

Citation Information: Drug Metabolism and Personalized Therapy, Volume 32, Issue 3, Pages 137–145, ISSN (Online) 2363-8915, ISSN (Print) 2363-8907, DOI: https://doi.org/10.1515/dmpt-2017-0018.

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