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Research ArticleArticle

Pharmacokinetic Interactions between Monoamine Oxidase A Inhibitor Harmaline and 5-Methoxy-N,N-Dimethyltryptamine, and the Impact of CYP2D6 Status

Xi-Ling Jiang, Hong-Wu Shen, Donald E. Mager and Ai-Ming Yu
Drug Metabolism and Disposition May 2013, 41 (5) 975-986; DOI: https://doi.org/10.1124/dmd.112.050724
Xi-Ling Jiang
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York
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Hong-Wu Shen
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York
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Donald E. Mager
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York
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Ai-Ming Yu
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York
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Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT or street name “5-MEO”) is a newer designer drug belonging to a group of naturally occurring indolealkylamines. Our recent study has demonstrated that coadministration of monoamine oxidase A (MAO-A) inhibitor harmaline (5 mg/kg) increases systemic exposure to 5-MeO-DMT (2 mg/kg) and active metabolite bufotenine. This study is aimed at delineating harmaline and 5-MeO-DMT pharmacokinetic (PK) interactions at multiple dose levels, as well as the impact of CYP2D6 that affects harmaline PK and determines 5-MeO-DMT O-demethylation to produce bufotenine. Our data revealed that inhibition of MAO-A–mediated metabolic elimination by harmaline (2, 5, and 15 mg/kg) led to a sharp increase in systemic and cerebral exposure to 5-MeO-DMT (2 and 10 mg/kg) at all dose combinations. A more pronounced effect on 5-MeO-DMT PK was associated with greater exposure to harmaline in wild-type mice than CYP2D6-humanized (Tg-CYP2D6) mice. Harmaline (5 mg/kg) also increased blood and brain bufotenine concentrations that were generally higher in Tg-CYP2D6 mice. Surprisingly, greater harmaline dose (15 mg/kg) reduced bufotenine levels. The in vivo inhibitory effect of harmaline on CYP2D6-catalyzed bufotenine formation was confirmed by in vitro study using purified CYP2D6. Given these findings, a unified PK model including the inhibition of MAO-A- and CYP2D6-catalyzed 5-MeO-DMT metabolism by harmaline was developed to describe blood harmaline, 5-MeO-DMT, and bufotenine PK profiles in both wild-type and Tg-CYP2D6 mouse models. This PK model may be further employed to predict harmaline and 5-MeO-DMT PK interactions at various doses, define the impact of CYP2D6 status, and drive harmaline–5-MeO-DMT pharmacodynamics.

Footnotes

    • Received December 19, 2012.
    • Accepted February 7, 2013.
  • X.-L.J. and H.-W.S. contributed equally to this work.

  • This research was supported by the National Institutes of Health National Institute on Drug Abuse [Grant R01-DA021172]. X.-L.J. was supported by a Pfizer fellowship.

  • dx.doi.org/10.1124/dmd.112.050724.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (5)
Drug Metabolism and Disposition
Vol. 41, Issue 5
1 May 2013
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Research ArticleArticle

Pharmacokinetic Interactions between Harmaline and 5-MeO-DMT

Xi-Ling Jiang, Hong-Wu Shen, Donald E. Mager and Ai-Ming Yu
Drug Metabolism and Disposition May 1, 2013, 41 (5) 975-986; DOI: https://doi.org/10.1124/dmd.112.050724

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Research ArticleArticle

Pharmacokinetic Interactions between Harmaline and 5-MeO-DMT

Xi-Ling Jiang, Hong-Wu Shen, Donald E. Mager and Ai-Ming Yu
Drug Metabolism and Disposition May 1, 2013, 41 (5) 975-986; DOI: https://doi.org/10.1124/dmd.112.050724
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