Metabolism and Pharmacogenetics in MDMA-Induced Toxicity

MDMA 引起的毒性的代谢和药物遗传学

• 批准号: 7125178
• 负责人: RAFAEL DE LA TORRE
• 金额: $ 18.46万
• 依托单位: MUNICIPAL INSTITUTE OF MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7125178
• 关键词: 3,4 methylenedioxymethamphetamine; blood brain barrier; caffeine; catechol methyltransferase; chemical conjugate; clinical research; cytochrome P450; dextromethorphan; drug metabolism; enzyme induction /repression; enzyme inhibitors; free radical oxygen; human subject; laboratory rat; liver metabolism; neural degeneration; neurotoxicology; neurotransmitter metabolism; oxidative stress; pharmacogenetics; probenecid; transport proteins

DESCRIPTION (provided by applicant): 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a synthetic compound structurally related to stimulants and hallucinogens. In the United States, in 2001, an estimated 3.6% of Americans aged 12 or older had tried ecstasy at least once in their lifetime (NHSDA). The frequency of recorded incidents associated with its acute toxicity is high. MDMA-related hospital emergency room incidents increased from 253 in 1994 to 4,511 in 2000 (SAMHSA Drug Abuse Warning Network). The potential neurodegeneration in subjects consuming MDMA is the most worrisome issue of its misuse. Although there is a growing consensus that MDMA is toxic to humans, the mechanisms underlying its toxic effects remain to be elucidated. Among the theories for the neurotoxic and acute toxic effects of MDMA, clinical and experimental data from animal models support the view that systemic metabolism contributes significantly to neurotoxicity. MDMA exhibits a non-linear pharmacokinetics in humans, a phenomenon related to its ability to inhibit its own metabolism (CYP2D6 is the enzyme involved) via the formation of an inactivating enzyme-metabolite complex. MDMA metabolites, which can generate oxygen free radicals, oxidative stress, and membrane damage, may contribute for the long-term MDMA-induced neurodegeneration. The key enzymes involved in MDMA metabolism are polymorphic (CYP2D6, COMT), exhibiting significant inter-individual and gender differences, which may contribute to differences in MDMA pharmacology and susceptibility to toxicity. A project is proposed that will study the metabolic factors involved in the toxicity of MDMA. To investigate the acute effects of MDMA, the project proposes to study the involvement of CYP2D6, CYP3A4 and CYP1A2 and COMT in MDMA metabolism. Particularly it is proposed to investigate the autoinhibition of CYP2D6 by MDMA and the contribution of other alternative CYP catalysed pathways. A clinical trial is proposed where MDMA will be administered in conjunction with probe drugs for CYP2D6 and CYP3A4 (dextromethorphan) and for CYP1A2 (caffeine). A separate trial is proposed whereby MDMA will be administered to individuals possessing poor or ultrarapid metabolism for CYP2D6. Physiological, and subjective effects, psychomotor performance, hormones and pharmacokinetics will be evaluated. Several animal studies in rats will compliment studies in humans. The development of neurotoxicity will be assessed co-administering MDMA with probe drugs, inhibitors of CYP2D6 and COMT activities. It has been postulated that the production of reactive oxygen species (ROS) is involved in the development of MDMA neurotoxicity. The metabolism of MDMA may contribute to the production of ROS through the formation of thioether-conjugates of catechol metabolites, whose formation in vivo in rats has been demonstrated. Transporters that regulate the efflux from hepatocytes and the passage through the blood brain barrier of conjugates such as MRP1 may play a role in MDMA neurotoxicity. Investigating the pharmacological implications of Phase III transporters would demonstrate the contribution of MDMA metabolism to mid-long term toxicity. A study will compare MDMA toxicity when co-adminsitered with the MRP1 inhibitor probenecid.

描述（由申请人提供）：3,4-亚甲基二氧基甲基苯丙胺（MDMA，摇头丸）是一种合成化合物，在结构上与兴奋剂和致幻剂有关。在美国，2001年，估计有3.6%的12岁以上的美国人在他们的一生中至少尝试过一次摇头丸（NHSDA）。与其急性毒性有关的记录事件频率很高。与mdma有关的医院急诊室事件从1994年的253起增加到2000年的4 511起（SAMHSA药物滥用警告网络）。服用MDMA的受试者潜在的神经退行性变是其滥用最令人担忧的问题。尽管越来越多的人认为MDMA对人体有毒，但其毒性作用的机制仍有待阐明。在关于MDMA神经毒性和急性毒性作用的理论中，来自动物模型的临床和实验数据支持全身代谢对神经毒性起重要作用的观点。MDMA在人体内表现出非线性药代动力学，这一现象与它通过形成失活酶-代谢物复合物来抑制自身代谢（CYP2D6是所涉及的酶）的能力有关。MDMA代谢物可产生氧自由基、氧化应激和膜损伤，可能是MDMA诱导的长期神经变性的原因之一。参与MDMA代谢的关键酶（CYP2D6、COMT）具有多态性，表现出显著的个体间和性别差异，这可能导致MDMA的药理学和毒性易感性的差异。提出了一个项目，将研究代谢因素参与MDMA的毒性。为探讨MDMA的急性作用，本项目拟研究CYP2D6、CYP3A4、CYP1A2及COMT参与MDMA代谢的机制。特别提出研究MDMA对CYP2D6的自抑制作用以及其他CYP催化途径的贡献。在一项临床试验中，MDMA将与CYP2D6和CYP3A4（右美沙芬）以及CYP1A2（咖啡因）的探针药物联合使用。一项单独的试验提出，MDMA将给予个体CYP2D6代谢不良或超快速。生理和主观效应，精神运动表现，激素和药代动力学将被评估。在大鼠身上进行的几项动物研究将对人类研究起到补充作用。将评估MDMA与探针药物、CYP2D6抑制剂和COMT活性抑制剂共同施用的神经毒性的发展。据推测，活性氧（ROS）的产生参与了MDMA神经毒性的发展。MDMA的代谢可能通过形成儿茶酚代谢物的硫醚偶联物来促进ROS的产生，其在大鼠体内的形成已被证实。调节肝细胞外排和MRP1等缀合物通过血脑屏障的转运蛋白可能在MDMA神经毒性中发挥作用。研究III期转运体的药理学意义将证明MDMA代谢对中长期毒性的贡献。一项研究将比较MDMA与MRP1抑制剂probenecid联合给药时的毒性。