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首页> 外文期刊>Biochemical Pharmacology >Effects of monoamine oxidase inhibitor and cytochrome P450 2D6 status on 5-methoxy-N,N-dimethyltryptamine metabolism and pharmacokinetics.
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Effects of monoamine oxidase inhibitor and cytochrome P450 2D6 status on 5-methoxy-N,N-dimethyltryptamine metabolism and pharmacokinetics.

机译：单胺氧化酶抑制剂和细胞色素P450 2D6状态对5-甲氧基-N，N-二甲基色胺的代谢和药代动力学的影响。

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摘要

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 (R(2)=0.98; P<0.0001) and CYP2D6 contents (R(2)=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 (20mg/kg, i.p.) had 60% higher systemic exposure to metabolite bufotenine. In addition, pretreatment of harmaline (5mg/kg, i.p.) led to 3.6- and 4.4-fold higher systemic exposure to 5-MeO-DMT (2mg/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.
机译：5-甲氧基-N，N-二甲基色胺（5-MeO-DMT）是一种天然的精神活性吲哚烷基胺药物，已用于娱乐目的。我们以前的研究表明，多态性细胞色素P450 2D6（CYP2D6）催化5-MeO-DMT O-去甲基化以产生活性代谢物丁丁烯碱，而5-MeO-DMT主要通过单胺氧化酶（MAO）介导的脱氨途径失活。因此，本研究旨在研究CYP2D6基因型/表型状态和MAO抑制剂（MAOI）对5-MeO-DMT代谢和药代动力学的影响。使用重组CYP2D6等位基因同工酶的酶动力学研究表明，从5-MeO-DMT生产丁丁烯碱中，CYP2D6.2和CYP2D6.10分别显示出低2.6和40倍的催化效率（V（max）/ K（m））。 ，与野生型CYP2D6.1相比。当与MAOI Pargyline共同孵育时，5-MeO-DMT O-去甲基化在10个人肝微粒体中显示与bufuralol 1'-羟化酶活性（R（2）= 0.98; P <0.0001）和CYP2D6含量（R（ 2）= 0.77; P = 0.0007），而与其他P450酶的酶活性没有明显的相关性。此外，在人CYP2D6广泛代谢者肝细胞中，同时发生的MAOI harmaline会显着降低5-MeO-DMT的消耗并增加丁苯丁胺的形成。在野生型和CYP2D6人源化（Tg-CYP2D6）小鼠模型中进行的体内研究表明，接受相同剂量的5-MeO-DMT（20mg / kg，ip）的Tg-CYP2D6小鼠全身性代谢产物丁丙泊汀的暴露量高60％ 。此外，对harmaline（5mg / kg，ip）的预处理导致5-MeO-DMT（2mg / kg，ip）的全身暴露分别高3.6倍和4.4倍，对丁苯丁宁的全身暴露分别高9.9和6.1倍在Tg-CYP2D6和野生型小鼠中分别存在。这些发现表明，MAOI在很大程度上影响5-MeO-DMT的代谢和药代动力学，以及由CYP2D6介导的丁苯丁胺的形成。

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