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Synthetic Cannabinoid Toxicity: Role of Biotransformation

合成大麻素毒性：生物转化的作用

基本信息

批准号：
9520656
负责人：
Paul L Prather
金额：
$ 4.35万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-15 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9520656
关键词：
Acute Adverse effects Affinity Agitation Agonist Auditory Hallucination Binding Biological Biological Assay Blood Brain CNR1 gene CNR2 gene Cannabinoids Chemicals Chinese Hamster Ovary Cell Chronic Clinical Complex Mixtures Cytochrome P450 Dangerousness Detection Drug Exposure Drug Kinetics Drug abuse Drug user Enzymes Formulation Glucuronosyltransferase Goals Government regulations Health Hepatic High Pressure Liquid Chromatography Human Hydroxylation In Vitro Individual Injection of therapeutic agent Intestines K2/Spice Kinetics Legal Life Marijuana Medical Metabolic Metabolic Biotransformation Metabolism Microsomes Mus Neuraxis Parents Patients Pharmaceutical Preparations Pharmacology Pharmacology and Toxicology Phase Physiological Plants Powder dose form Property Protein Isoforms Public Health Reporting Risk Role Safety Sampling Seizures Smoke Symptoms Syncope Tablets Tachycardia Teenagers Testing Tetrahydrocannabinol Therapeutic Time Toxic effect Urine Visual Hallucination acute toxicity associated symptom cannabimimetics capsule clinical effect design drug of abuse experience experimental study in vivo male marijuana legalization marijuana use metabolic profile nanomolar public health relevance receptor sulfotransferase synthetic cannabinoid

项目摘要

DESCRIPTION (provided by applicant): The terms "K2" and "Spice" refer to any number of commercial products usually sold as "legal marijuana". These products contain dangerous synthetic cannabinoid (SCBs) that are presumed to possess psychoactive properties similar to ∆9-tetrahydrocannabinol (∆9-THC), the natural cannabinoid found in marijuana. ∆9-THC and SCBs both produce psychotropic actions by activating CB1 cannabinoid receptors (CB1Rs) in the CNS. However, SCBs are a chemically diverse group of compounds that are structurally distinct from ∆9-THC, and thus detection of their use is difficult and has led to widespread abuse. Medical use of marijuana and ∆9-THC has been shown to be safe. In marked contrast, no information is known concerning the safety or efficacy of any SCB found in K2, and reports suggest that many clinical effects of K2 products are distinct from those produced by marijuana and may present health risks. In this regard, our preliminary analysis of urine samples from SCB users by LC-MS/MS suggests that levels of SCB metabolites correlate with clinical symptoms that may be life threatening. Furthermore, we reported that several hydroxylated metabolites of SCBs retain high affinity and activity at CB1R and CB2Rs, and dramatically increase acute effects of parent SCBs. Therefore, in an individual user, the physiological effects of SCBs may represent an "entourage" effect caused 1) by the distinct blend of SCBs in a given product, and 2) further influenced by the individual's metabolic capacity to transform SCBs into distinct Phase I and II active metabolites. Thus, it is important to define the metabolic profile of SCBs in humans and their biological activity at CB1Rs and CB2Rs. The goal of this project is to elucidate the biodisposition, biotransformation, and biological activity of SCBs and their metabolites at CB1Rs and CB2Rs in humans, and correlate these findings with acute and chronic adverse effects in mice. We will test the hypothesis that in vivo hydroxylation of SCBs by cytochromes P450 (CYPs) and subsequent conjugation by UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) produces a complex mixture of high affinity CB1R and CB2R agonists, antagonists, and inverse agonists. These metabolites acting "in concert" with parent SCBs produce the distinct pharmacologic effects and toxicity of SCBs in humans. Our interdisciplinary team will explore this hypothesis by four Specific Aims. Aim 1 will employ LC-MS/MS to identify in human urine the primary and secondary metabolites of 9 high priority SCBs abused in K2 products. Clinical symptom profiles will also be collected for each patient. Experiments in Aim 2 will characterize the human Phase I and II enzymes responsible for the in vitro metabolism of SCBs. In Aim 3, SCBs and their metabolites will be examined for the ability to bind to and activate human CB1Rs and CB2Rs. Finally, studies in Aim 4 will determine the pharmacokinetic profile of SCBs and determine if these compounds and their metabolites elicit cannabimimetic effects in mice. This collaborative translational project will provide information concerning the metabolism, pharmacology and toxicology of SCBs to identify likely health risks to the public.