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, Aiming Yu

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 Odemethylation 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.

Original languageEnglish (US)
Pages (from-to)975-986
Number of pages12
JournalDrug Metabolism and Disposition
Volume41
Issue number5
DOIs
StatePublished - May 2013
Externally publishedYes

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N,N-Dimethyltryptamine
Harmaline
Cytochrome P-450 CYP2D6
Monoamine Oxidase Inhibitors
Bufotenin
Pharmacokinetics
Monoamine Oxidase
Methoxydimethyltryptamines
Designer Drugs

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Pharmacokinetic interactions between monoamine oxidase a inhibitor harmaline and 5-methoxy-n,n-dimethyltryptamine, and the impact of CYP2D6 status. / Jiang, Xi Ling; Shen, Hong Wu; Mager, Donald E.; Yu, Aiming.

In: Drug Metabolism and Disposition, Vol. 41, No. 5, 05.2013, p. 975-986.

Research output: Contribution to journalArticle

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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 Odemethylation 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.",
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