Effects of monoamine oxidase inhibitor and cytochrome P450 2D6 status on 5-methoxy-N,N-dimethyltryptamine metabolism and pharmacokinetics

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural psychoactive indolealkylamine drug that has been used for recreational purpose. Our previous study revealed that polymorphic cytochrome P450 2D6 (CYP2D6) catalyzed 5-MeO-DMT O-demethylation to produce active metabolite bufotenine, while 5-MeO-DMT is mainly inactivated through deamination pathway mediated by monoamine oxidase (MAO). This study, therefore, aimed to investigate the impact of CYP2D6 genotype/phenotype status and MAO inhibitor (MAOI) on 5-MeO-DMT metabolism and pharmacokinetics. Enzyme kinetic studies using recombinant CYP2D6 allelic isozymes showed that CYP2D6.2 and CYP2D6.10 exhibited 2.6-and 40-fold lower catalytic efficiency (V max /K m ), respectively, in producing bufotenine from 5-MeO-DMT, compared with wild-type CYP2D6.1. When co-incubated with MAOI pargyline, 5-MeO-DMT O-demethylation in 10 human liver microsomes showed significantly strong correlation with bufuralol 1'-hydroxylase activities (R² = 0.98; p < 0.0001) and CYP2D6 contents (R² = 0.77; p = 0.0007), whereas no appreciable correlations with enzymatic activities of other P450 enzymes. Furthermore, concurrent MAOI harmaline sharply reduced 5-MeO-DMT depletion and increased bufotenine formation in human CYP2D6 extensive metabolizer hepatocytes. In vivo studies in wild-type and CYP2D6-humanized (Tg-CYP2D6) mouse models showed that Tg-CYP2D6 mice receiving the same dose of 5-MeO-DMT (20 mg/kg, i.p.) had 60% higher systemic exposure to metabolite bufotenine. In addition, pre-treatment of harmaline (5 mg/kg, i.p.) led to 3.6-and 4.4-fold higher systemic exposure to 5-MeO-DMT (2 mg/kg, i.p.), and 9.9-and 6.1-fold higher systemic exposure to bufotenine in Tg-CYP2D6 and wild-type mice, respectively. These findings indicate that MAOI largely affects 5-MeO-DMT metabolism and pharmacokinetics, as well as bufotenine formation that is mediated by CYP2D6.

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

“…Indeed, our recent studies (Shen et al, 2010b) support the metabolic DDI between MAOI and 5-MeO-DMT, as manifested by the reduction of 5-MeO-DMT depletion in human liver microsomes and elevation of 5-MeO-DMT exposure in animal models by concurrent harmaline exposure. Furthermore, the blockage of MAO-A-controlled deamination metabolism may result in an enhanced O-demethylation of 5-MeO-DMT (Shen et al, 2010b), which is catalyzed by polymorphic CYP2D6 (Zanger et al, 2004) to generate bufotenine (Yu et al, 2003a), an active metabolite with 10-fold higher affinity to the 5-HT 2A receptor than 5-MeO-DMT (Roth et al, 1997). In addition, the PK of harmaline is affected by CYP2D6 status, as demonstrated by a faster systemic clearance in CYP2D6-humanized (Tg-CYP2D6) mice than that in wild-type mice (Yu et al, 2003b;Wu et al, 2009).…”

“…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.…”

“…Serum bufotenine concentrations were also determined to define the impact of harmaline on 5-MeO-DMT O-demethylation that is mediated by CYP2D6 enzyme (Yu et al, 2003a;Shen et al, 2010b). In both wild-type and Tg-CYP2D6 mice, coadministration of a lower dose (5 mg/kg) of harmaline significantly increased bufotenine production from 5-MeO-DMT.…”

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

“…The low urinary recovery and biliary excretion of substrate drug indicate that 5-MeO-DMT is predominantly eliminated through metabolism (Agurell et al, 1969;Sitaram et al, 1987a). In vitro and in vivo studies show that MAO-A-mediated deamination is the major metabolic pathway for 5-MeO-DMT, whereas other metabolic pathways such as N-oxygenation, N-demethylation, and O-demethylation were also reported (Agurell et al, 1969;Squires, 1975;Sitaram et al, 1987a,b;Shen et al, 2009Shen et al, , 2010b. The O-demethylation mediated by CYP2D6 produces an active metabolite, bufotenine (Yu et al, 2003a).…”

“…Limited pharmacokinetic studies using mouse or rat models suggest that 5-MeO-DMT is rapidly absorbed and eliminated (Sitaram et al, 1987a,b;Shen et al, 2009Shen et al, , 2010b. The low urinary recovery and biliary excretion of substrate drug indicate that 5-MeO-DMT is predominantly eliminated through metabolism (Agurell et al, 1969;Sitaram et al, 1987a).…”