Nonlinear Pharmacokinetics of 5-Methoxy-<i>N,N</i>-dimethyltryptamine in Mice

Shen, Hong; Jiang, Xi Ling; Yu, Aiming

doi:10.1124/dmd.111.039107

Cited by 25 publications

(30 citation statements)

References 37 publications

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“…and i.p. administration of 5-MeO-DMT (2, 10, or 20mg/kg) alone (Shen et al, 2011b) as well as i.v. and i.p.…”

Section: Methodsmentioning

confidence: 99%

“…Experiments were conducted as previously reported (Shen et al, 2011b). Briefly, wild-type and Tg-CYP2D6 mice (n = 4 per time point) were euthanized at various time points after drug administration.…”

Section: Methodsmentioning

confidence: 99%

“…Pharmacokinetic experiments were conducted as previously reported (Shen et al, 2010b(Shen et al, , 2011b. To define the impact of MAOI harmaline on 5-MeO-DMT PK, wild-type and Tg-CYP2D6 mice were treated i.p.…”

Section: Methodsmentioning

confidence: 99%

“…Blood and brain drug and metabolite concentrations were determined by a validated LC-MS/MS method (Shen et al, , 2011b. A simple protein precipitation and a liquid-liquid extraction method were used for the processing of serum and brain samples, respectively.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2013

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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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“…and i.p. administration of 5-MeO-DMT (2, 10, or 20mg/kg) alone (Shen et al, 2011b) as well as i.v. and i.p.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

et al. 2013

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“…This article allowed for pharmacokinetic parameters to be estimated from the data which can aid with drug design. A three compartment model was applied to mouse data in Shen et al (2011) where the link between 5-methoxy-N,N-dimethyltryptamine metabolism and the CYP2D6 enzyme was studied. Their model describe a nonlinear elimination from the central compartment based on Michaelis-Menten kinetics and the peripheral compartment is solely to represent the CYP2D6 dependent metabolism.…”

Section: Introductionmentioning

confidence: 99%

The usage of a three-compartment model to investigate the metabolic differences between hepatic reductase null and wild-type mice

Hill

Chaplain

Wolf

et al. 2015

Mathematical Medicine and Biology: A Journal of the IMA

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The Cytochrome P450 (CYP) system is involved in 90% of the human bodys interactions with xenobiotics and due to this it has become an area of avid research including the creation of transgenic mice. This paper proposes a three compartment model which is used to explain the drug metabolism in the Hepatic Reductase Null (HRN) mouse developed by the University of Dundee (Henderson et al., 2003). The model is compared with a two compartment model using experimental data from studies using wild type and HRN mice. This comparison allowed for metabolic differences between the two types of mice to be isolated. The three sets of drug data (Gefitinib, Midazolam and Thalidomide) showed that the transgenic mouse has a decreased rate of metabolism.

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Ayahuasca, Harmala Alkaloids, and Dimethyltryptamines

Barceloux

2012

Medical Toxicology of Drug Abuse

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Nonlinear Pharmacokinetics of 5-Methoxy-N,N-dimethyltryptamine in Mice

Cited by 25 publications

References 37 publications

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

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

The usage of a three-compartment model to investigate the metabolic differences between hepatic reductase null and wild-type mice

Ayahuasca, Harmala Alkaloids, and Dimethyltryptamines

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