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: 10004986
• 负责人: Michael Baumann
• 金额: $ 112.24万
• 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/10004986
• 关键词: Adverse effects; Area Under Curve; Bathing; Binding; Biological Assay; Blood specimen; Catalepsy; Catheters; Conscious; Coupled; Data; Designer Drugs; Detection; Dopamine; Dose; Drug Kinetics; Fentanyl; Goals; Guidelines; Half-Life; Heroin; High Pressure Liquid Chromatography; Human; Impairment; In Vitro; K2/Spice; Kinetics; Lead; Life; Liquid substance; Measures; Methods; Microdialysis; Molecular Mechanisms of Action; Morphine; Naloxone; Neurons; Opioid; Overdose; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacology and Toxicology; Plasma; Poison; Public Health; Publishing; Rattus; Research; Research Project Grants; Risk; Saline; Salts; Sampling; Self Administration; Serotonin; Sprague-Dawley Rats; Street Drugs; Substance abuse problem; Temperature; Time; addiction; analog; analytical method; behavioral study; biological systems; carfentanil; cathinone; clinically relevant; drug metabolism; drug of abuse; extracellular; in vivo; interest; male; natural hypothermia; opioid overdose; overdose death; pharmacokinetics and pharmacodynamics; radioligand; subcutaneous; synthetic cannabinoid; synthetic drug; synthetic opioid; tandem mass spectrometry

Summary- Substantial progress was made on this project, with six original research articles and two 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 pharmacodynamics and pharmacokinetics of carfentanil, an ultrapotent fentanyl analog that has been implicated in hundreds of overdose deaths. Importantly, we show that carfentanil displays non-linear kinetics after systemic administration in rats, suggesting impaired clearance for this toxic substance. The current opioid overdose crisis is being exacerbated by illicitly manufactured fentanyl and its analogs. Carfentanil is a fentanyl analog that is 10,000-times more potent than morphine, but limited information is available about its pharmacology. Our study had two aims: 1) to validate a method for quantifying carfentanil and its metabolite norcarfentanil in small-volume samples, and 2) to use the method for examining pharmacodynamic-pharmacokinetic relationships in rats. The analytical method involved liquid-liquid extraction of plasma samples followed by quantitation of carfentanil and norcarfentanil using ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). The method was validated following SWGTOX guidelines, and both analytes displayed limits of detection and quantification at 7.5 and 15 pg/mL, respectively. Male Sprague-Dawley rats fitted with jugular catheters and temperature transponders received subcutaneous carfentanil (1, 3 and 10 ug/kg) or saline. Repeated blood specimens were obtained over 8h, along with pharmacodynamic measures including core temperature and catalepsy scores. Carfentanil produced dose-related hypothermia and catalepsy that lasted up to 8h. Carfentanil Cmax occurred at 15min whereas metabolite Cmax was at 1-2h. Concentrations of both analytes increased in a dose-related fashion, but area-under-the-curve values were much greater than predicted after 10 ug/kg. Plasma half-life for carfentanil increased at higher doses. Our findings reveal that carfentanil produces marked hypothermia and catalepsy, which is accompanied by nonlinear accumulation of the drug at high doses. We hypothesize that impaired clearance of carfentanil in humans could contribute to life-threatening effects and lead to re-narcotization after initial naloxone rescue.

在该项目上取得了巨大的进展，并发表了六篇原始研究文章和两份评论。与我们的合作者一起，我们还表征了在街头药物市场中发现的许多合成大麻素，Cathinones和阿片类药物的药理作用。在一项代表性的研究中，我们描述了Carfentanil的药效学和药代动力学，Carfentanil是一种超能力的芬太尼类似物，涉及数百例过量死亡。重要的是，我们表明Carfentanil在大鼠全身给药后显示非线性动力学，这表明这种有毒物质的清除受损。 当前的阿片类药物过量危机正在因非法制造的芬太尼及其类似物而加剧。 Carfentanil是一种芬太尼类似物，比吗啡高10,000倍，但有关其药理学的信息有限。我们的研究有两个目的：1）验证一种在小体积样本中量化Carfentanil及其代谢物Norcarfentanil的方法，以及2）使用该方法检查大鼠的药效学 - 疗法关系。分析方法涉及血浆样品的液液提取，然后使用超高绩效的液相色谱法（UHPLC-MS/MS）定量carfentanil和Norcarfentanil。根据SWGTOX指南对该方法进行了验证，两种分析物分别在7.5和15 pg/mL处显示出检测和定量的限制。雄性Sprague-Dawley大鼠装有颈导导管和温度转发器的大鼠接受皮下Carfentanil（1、3和10 ug/kg）或盐水。重复的血液样本在8H上获得了重复的样本，以及包括核心温度和催眠评分在内的药效学指标。 Carfentanil产生了与剂量相关的体温过低和持续8小时的血症。 Carfentanil Cmax发生在15分钟时，而代谢物CMAX为1-2H。两种分析物的浓度都以剂量相关的方式增加，但是曲线以下的区域值远大于10 ug/kg后的预测。 Carfentanil的血浆半衰期在较高剂量时增加。我们的发现表明，Carfentanil会产生明显的体温过低和培养病，并伴随着高剂量的非线性积累。我们假设在人类中的carfentanil清除率受损可能会导致威胁生命的影响，并在最初的Naloxone救援后导致重新解剖。