Kratom alkaloids: in vitro and in vivo pharmacological mechanisms

卡痛生物碱：体外和体内药理机制

• 批准号: 10754688
• 负责人: Christopher R McCurdy
• 金额: $ 7.27万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10754688
• 关键词: Adrenergic Agonists; Adrenergic Receptor; Agonist; Alkaloids; Animals; Applications Grants; Behavior assessment; Behavioral; Binding; Biological; Biological Assay; Biological Availability; Brain; CYP3A4 gene; Chemical Structure; Chemicals; Chromatography; Complex; Computer Models; Computer software; Data; Dose; Drug Kinetics; Drug Modelings; Drug usage; Dryness; Enzymes; Exhibits; Explosion; Female; Fentanyl; Gold; Health; Heroin; In Vitro; Individual; Laboratories; Liver; Liver Microsomes; Marketing; Mediating; Metabolic Pathway; Metabolism; Methadone; Methods; Microsomes; Minor; Mitragyna; Modeling; Naltrexone; Natural Products Chemistry; Opiate Addiction; Opioid; Opioid Receptor; Parents; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Plant Leaves; Plants; Plasma; Rattus; Recombinants; Risk; Self Administration; Source; Stimulus; System; Techniques; Testing; Toxic effect; Training; Translations; Trees; United States Food and Drug Administration; Urine; abuse liability; antagonist; capsule; drug discrimination; in vivo; inhibitor; male; non-opioid analgesic; opioid abuse; pharmacokinetics and pharmacodynamics; pharmacologic; receptor; remifentanil; sex

Mitragyna speciosa (kratom) has exploded onto the US market, with an estimated 55,000 kg entering the US between 2014 and 2016, corresponding to 12 million kratom doses and one million users. The FDA recently used computational modeling to predict that 22 kratom constituents bind to opioid receptors; however, these predictions await translation into whole animals. There is an urgent need for systematic, pharmacological testing of kratom alkaloids to help inform abuse risk. We feel it is important to assess the behavioral effects of not only individual alkaloids, but also alkaloid mixtures representative of plant material in commercially used products. We will extract, isolate, and purify alkaloids from two kratom sources: dried leaf material of Mitragyna speciosa trees and a US commercial product (i.e., OPMS Gold capsules). We will quantify up to ten kratom alkaloids simultaneously using our bioanalytical methods. In a pharmacokinetic-based Aim 1, we will quantify kratom alkaloids in multiple biological matrices (urine, plasma, brain, liver) after p.o. and i.v. administration in rats to obtain a comprehensive ADME profile. Liver microsomes, recombinant CYP450 enzymes, and specific chemical CYP450 inhibitors will be used to identify pathways of metabolism and biologically active metabolites. In our pharmacodynamic-based Aim 2, we will use drug discrimination to identify receptor mechanism(s) underlying abuse-related effects. Four separate groups of rats will be trained to discriminate one of the following: 1) alkaloid mixture in proportion to kratom dried leaf material, 2) alkaloid mixture in proportion to commercially available kratom product (both containing 32 mg/kg mitragynine, 3) 32 mg/kg mitragynine alone, or 4) 3.2 mg/kg 7- hydroxymitragynine alone. Moreover, we will use i.v. drug self-administration to assess abuse risk, and to assess how kratom alkaloids modify the reinforcing effects of abused opioids (i.e., heroin). Male and female rats will be used throughout to assess sex as a biological variable. The overarching hypothesis is that Mitragyna speciosa has a complex pharmacology resulting from multiple alkaloids differentially interacting with both opioid and non- opioid receptors. The following specific hypotheses will be tested: 1) alkaloids interact (i.e., exert synergistic and antagonist effects) with each other and with other abused opioids in drug discrimination and self-administration assays; 2) some of the interactions are due to PK; 3) behavioral effects of the parent alkaloid are due in part to both the parent compound and its behaviorally active metabolites; 4) no single alkaloid accounts for the discriminative stimulus and reinforcing effects of the mixtures; and 5) both opioid and adrenergic receptors mediate the effects of alkaloid mixtures representative of natural plant material. Subtraction and addition of individual alkaloids will help identify the alkaloids most responsible for kratom's integrated pharmacology. After 5 years, we expect to demonstrate that kratom alkaloids exert differential effects through multiple receptor systems, and we further expect to identify key pharmacological mechanisms responsible for the widespread use of kratom.

大金鱼已经进入美国市场，据估计有55000公斤进入美国 2014至2016年间，相当于1200万剂KrATOM剂量和100万用户。美国食品和药物管理局最近 使用计算模型预测22种Krtom成分与阿片受体结合；然而，这些 预测有待转化为完整的动物。迫切需要进行系统的药理学测试。 Krtom生物碱有助于告知滥用风险。我们认为，重要的是评估不仅是 单独的生物碱，但也有代表商业使用产品中的植物材料的生物碱混合物。 我们将从两个KrATOM来源中提取、分离和纯化生物碱：三叶草的干燥叶材料 树和一种美国商业产品(即OPMS黄金胶囊)。我们将对多达10种Krtom生物碱进行定量 同时使用我们的生物分析方法。在基于药代动力学的目标1中，我们将量化KrATOM P.O.多种生物基质(尿、血浆、脑、肝)中的生物碱和静脉注射。在大鼠体内给药 获取全面的ADME简档。肝微粒体、重组细胞色素P450酶和特定化学物质 细胞色素P450抑制剂将用于确定代谢途径和生物活性代谢物。在我们的 以药效学为基础的目标2，我们将用药物辨别来确定受体机制(S)的潜在原因 与滥用有关的影响。将对四组不同的大鼠进行训练，以区分以下其中一种：1)生物碱 按Krtom干燥叶材料的比例混合，2)按商品可得的生物碱混合比例 KrATOM产品(均含有32毫克/公斤的三叶草碱，3)32毫克/公斤的三叶草碱，或4)3.2毫克/公斤的7- 单独使用羟基米曲吉宁。此外，我们将使用静脉注射。药物自我管理以评估滥用风险，并评估 Krtom生物碱如何改变滥用阿片类药物(即海洛因)的增强效应。雄鼠和雌鼠将是 从头到尾都被用来评估性别作为一个生物变量。最重要的假设是，大花叶蝉 具有复杂的药理作用，由多种生物碱与阿片类药物和非阿片类药物不同地相互作用而产生 阿片受体。将检验以下具体假设：1)生物碱相互作用(即，发挥协同作用和 相互之间以及与其他滥用的阿片类药物在药物辨别和自我给药中的相互作用 分析；2)一些相互作用是由于PK；3)亲本生物碱的行为效应部分是由于 母体化合物及其行为活性代谢物；4)没有单一的生物碱能解释 5)阿片受体和肾上腺素能受体 调节以天然植物材料为代表的生物碱混合物的效果。减法和加法 个别生物碱将有助于确定对Krtom的综合药理最负责的生物碱。之后 5年后，我们希望证明Krtom生物碱通过多个受体发挥不同的作用。 系统，我们进一步期望确定导致这种广泛使用的关键药理机制 KrATOM。