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Kratom alkaloids: in vitro and in vivo pharmacological mechanisms

卡痛生物碱：体外和体内药理机制

基本信息

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
项目类别：
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

项目摘要

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.

Mitragyna speciosa（kratom）在美国市场上爆炸式增长，估计有55，000公斤进入美国 2014年至2016年，相当于1 200万kratom剂量和100万用户。FDA最近使用计算模型预测22种kratom成分与阿片受体结合;然而，这些预测等待翻译成整个动物。迫切需要进行系统的药理学测试 kratom生物碱，以帮助告知滥用风险。我们认为重要的是评估行为影响，不仅单独的生物碱，以及代表商业使用产品中植物材料的生物碱混合物。我们将从两种kratom来源中提取、分离和纯化生物碱：树木和美国商业产品（即，OPMS Gold胶囊）。我们将量化多达10 kratom生物碱同时使用我们的生物分析方法。在基于动力学的目标1中，我们将量化kratom 口服后多种生物基质（尿液、血浆、脑、肝脏）中的生物碱和大鼠静脉内给药，获取全面的ADME配置文件。肝微粒体、重组CYP 450酶和特定化学品 CYP 450抑制剂将用于鉴定代谢途径和生物活性代谢物。在我们基于药效学的目标2，我们将使用药物区分来确定潜在的受体机制与滥用有关的影响。将训练四个单独的大鼠组来区分以下之一：与kratom干燥叶材料成比例的混合物，2）与市售可得的生物碱混合物成比例的生物碱混合物， kratom产品（均含有32 mg/kg mitragynine，3）单独32 mg/kg mitragynine，或4）3.2 mg/kg 7- 单独使用羟基米曲宁。此外，我们将使用静脉注射药物自我管理来评估滥用风险，并评估 Kratom生物碱如何改变滥用阿片样物质的增强作用（即，海洛因）。雄性和雌性大鼠将用于评估性别作为一个生物变量。总体假设是美丽帽柱木具有复杂的药理学，这是由于多种生物碱与阿片样物质和非阿片样物质有差异地相互作用而导致的。阿片受体将测试以下特定假设：1）生物碱相互作用（即，发挥协同作用，拮抗剂效应）以及与其他滥用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）母体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）没有单一的生物碱占混合物的辨别刺激和强化作用; 5）阿片受体和肾上腺素能受体介导代表天然植物材料的生物碱混合物的作用。减法和加法个别生物碱将有助于确定kratom的综合药理学最负责的生物碱。后 5年来，我们希望证明kratom生物碱通过多种受体发挥不同的作用，系统，我们进一步期望确定负责广泛使用的关键药理学机制关于Kratom