Pharmacology and toxicology of newly-emerging designer drugs of abuse

新兴设计滥用药物的药理学和毒理学

• 批准号: 9551869
• 负责人: Michael Baumann
• 金额: $ 111.6万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9551869
• 关键词: Adverse effects; Area Under Curve; Bathing; Binding; Biological; Biological Assay; Blood specimen; Brain; Catheters; Conscious; Data; Designer Drugs; Dopamine; Dose; Drug Kinetics; Goals; Heroin; Human; In Vitro; Intravenous; K2/Spice; Kinetics; Life; Liquid Chromatography; Metabolism; Methamphetamine; Methods; Microdialysis; Molecular Mechanisms of Action; Neurons; Nucleus Accumbens; Opioid; Overdose; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Phase; Plasma; Public Health; Publishing; Rattus; Research; Research Project Grants; Risk; Salts; Self Administration; Serotonin; Specimen; Street Drugs; Substance abuse problem; Testing; addiction; analog; behavioral study; biological systems; cathinone; clinically relevant; drug metabolism; drug of abuse; ecstasy; experimental study; extracellular; in vivo; interest; male; monoamine; pill; radioligand; subcutaneous; synthetic cannabinoid; synthetic drug; tandem mass spectrometry

Summary- Substantial progress was made on this project, with five original research articles and three reviews published. Along with our collaborators, we have characterized the pharmacological effects of numerous synthetic cannabinoids, cathinones and opioids found in the street drug marketplace. In a representative study, we described the molecular mechanism of action and pharmacological effects for the bath salts constituent methylone and its various metabolites. Methylone is constituent of products sold on the street as MDMA (i.e., counterfeit Ecstasy pills). Our findings from rat experiments show that methylone is extensively metabolized in a manner similar to MDMA. In particular, methylone displays non-linear kinetics after systemic administration, whereby plasma drug concentrations are much greater than dose-proportional. The N-demethylated metabolite, 3,4-methylenedioxycathinone is a potent transporter releaser in vitro and in vivo, suggesting this metabolite can contribute to effects of systemically administered methylone. Our findings in rats highlight the inherent risks to human users who inadvertently abuse methylone as a constituent of counterfiet Ecstasy pills. 3,4-Methylenedioxy-N-methylcathinone (methylone) is a new psychoactive substance and the -keto analog of 3,4-methylenedioxy-N-methylamphetamine (MDMA). It is well established that MDMA metabolism produces bioactive metabolites. Here we tested the hypothesis that methylone metabolism in rats can form bioactive metabolites. First, we examined the pharmacokinetics (PKs) of methylone and its metabolites after subcutaneous (sc) methylone administration (3, 6, 12mg/kg) to male rats fitted with intravenous (iv) catheters for repeated blood sampling. Plasma specimens were assayed by liquid chromatography tandem mass spectrometry to quantify methylone and its phase I metabolites: 3,4-methylenedioxycathinone (MDC), 3,4-dihydroxy-N-methylcathinone (HHMC), and 4-hydroxy-3-methoxy-N-methylcathinone (HMMC). The biological activity of methylone and its metabolites was then compared using in vitro transporter assays and in vivo microdialysis in rat nucleus accumbens. For the PK study, we found that methylone and MDC peaked early (Tmax=15-45min) and were short lived (t1/2=60-90min), while HHMC and HMMC peaked later (Tmax=60-120min) and persisted (t1/2=120-180min). Area-under-the-curve values for methylone and MDC were greater than dose-proportional, suggesting non-linear accumulation. Methylone produced significant locomotor activation, which was correlated with plasma methylone, MDC, and HHMC concentrations. Methylone, MDC, and HHMC were substrate-type releasers at monoamine transporters as determined in vitro, but only methylone and MDC (1, 3mg/kg, iv) produced significant elevations in brain extracellular dopamine and 5-HT in vivo. Our findings demonstrate that methylone is extensively metabolized in rats, but MDC is the only centrally active metabolite that could contribute to overall effects of the drug in vivo.

摘要--该项目取得了实质性进展，发表了五篇原创研究文章和三篇综述。与我们的合作者一起，我们描述了街头毒品市场上发现的许多合成大麻素、卡西尼酮和阿片类药物的药理作用。在一项具有代表性的研究中，我们描述了浴盐成分甲酮及其各种代谢物的分子作用机制和药理作用。甲基酮是街头销售的MDMA(即假冒摇头丸)产品的组成部分。我们从老鼠实验中的发现表明，甲酮以类似于MDMA的方式广泛代谢。特别是，甲酮在全身给药后表现出非线性动力学，即血浆药物浓度远远大于剂量比例。N-去甲基化的代谢物3，4-亚甲基二氧基卡西酮在体外和体内都是一种有效的转运蛋白释放剂，这表明这种代谢物可能参与了全身给药的效应。我们在大鼠身上的发现突显了人类使用者的内在风险，他们无意中滥用甲酮作为摇头丸的成分。 3，4-亚甲二氧基-N-甲基苯丙酮(简称甲酮)是一种新的精神活性物质，是3，4-亚甲二氧基-N-甲基苯丙胺(MDMA)的类似物。众所周知，MDMA代谢会产生生物活性代谢物。在这里，我们测试了一种假设，即大鼠体内的甲酮代谢可以形成生物活性代谢物。首先，我们研究了皮下注射(Sc)甲酮(3，6，12 mg/kg)后甲酮及其代谢物的药代动力学(PKs)。血浆样品用液相色谱-串联质谱法测定甲酮及其I相代谢产物：3，4-亚甲基二氧基卡西酮(MDC)、3，4-二羟基-N-甲基卡西酮(HHMC)和4-羟基-3-甲氧基-N-甲基卡西酮(HMMC)。用体外转运体实验和体内微透析法比较甲酮及其代谢产物在大鼠伏隔核的生物活性。在PK研究中，我们发现甲基酮和MDC的峰值较早(Tmax=15-45min)且持续时间较短(T1/2=60-90min)，而HHMC和HMMC的峰值较晚(Tmax=60-120min)，并持续存在(T1/2=120-180min)。甲酮和MDC的曲线下面积值大于剂量比例，表明存在非线性累积。甲酮引起显著的运动激活，这与血浆甲酮、MDC和HHMC浓度相关。体外实验表明，甲酮、MDC和HHMC是单胺转运体的底物型释放剂，但体内只有甲酮和MDC(1，3 mg/kg，iv)能显著增加脑细胞外多巴胺和5-羟色胺的释放。我们的发现表明，甲酮在大鼠体内被广泛代谢，但MDC是唯一可能对药物在体内的整体效应做出贡献的中枢活性代谢物。