title: Pharmacokinetic interactions between monoamine oxidase A inhibitor harmaline and 5-methoxy-N,N-dimethyltryptamine, and the impact of CYP2D6 status.
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.
authors: Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York, USA.
authors: Xi-Ling
authors: XL
authors: Jiang
authors: Hong-Wu
authors: HW
authors: Shen
authors: Donald E
authors: DE
authors: Mager
authors: Ai-Ming
authors: AM
authors: Yu
mesh_terms: D000818:Animals; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006246:Harmaline / Q000097:blood / Q000493:pharmacokinetics*; D008732:Methoxydimethyltryptamines / Q000493:pharmacokinetics*; D051379:Mice; D008822:Mice, Transgenic; D008995:Monoamine Oxidase / Q000187:drug effects; D008996:Monoamine Oxidase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry
chemical_list: D008732:Methoxydimethyltryptamines; D008996:Monoamine Oxidase Inhibitors; D006246:Harmaline; D019389:Cytochrome P-450 CYP2D6; D008995:Monoamine Oxidase
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