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.

摘要--该项目取得了实质性进展，发表了六篇原创研究文章和两篇综述。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，我们描述了卡芬太尼的药效学和药代动力学，卡芬太尼是一种超强的芬太尼类似物，已与数百例过量死亡有关。重要的是，我们发现卡芬太尼在大鼠全身给药后表现出非线性动力学，表明这种有毒物质的清除受到损害。 非法制造的芬太尼及其类似物加剧了目前的阿片类药物过量危机。卡芬太尼是一种芬太尼类似物，其效力是吗啡的1万倍，但有关其药理的信息有限。我们的研究有两个目的：1)验证卡芬太尼及其代谢物去甲芬太尼在小体积样品中的定量方法；2)用该方法研究大鼠体内的药效学-药动学关系。该分析方法包括血浆样品的液-液萃取，然后使用超高效液相色谱-串联质谱仪(UHPLC-MS/MS)对卡芬太尼和去甲卡芬太尼进行定量。该方法按照SWGTOX指南进行验证，两种分析物的检出限和定量限分别为7.5和15pg/mL。装有颈静脉导管和温度应答器的雄性SD大鼠接受皮下注射卡芬太尼(1、3和10ug/kg)或生理盐水。在8小时内采集重复的血样，并进行药效学测量，包括核心体温和嗜睡评分。卡芬太尼引起剂量相关的体温下降和眩晕，持续时间长达8小时。卡芬太尼Cmax出现在15min，而代谢物Cmax出现在1~2 h。这两种分析物的浓度都以与剂量相关的方式增加，但曲线下面积值在10ug/kg之后比预期的要大得多。卡芬太尼的血浆半衰期随剂量增加而延长。我们的研究结果表明，卡芬太尼会产生明显的体温过低和过敏症，并伴随着药物在高剂量下的非线性累积。我们推测，卡芬太尼在人体内的清除障碍可能会导致危及生命的效应，并导致最初的纳洛酮抢救后再次麻醉。