Drug-drug interactions between cannabis and hydrocodone.

大麻和氢可酮之间的药物相互作用。

• 批准号: 10536444
• 负责人: Shelby Coates
• 金额: $ 3.85万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2025-08-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536444
• 关键词: Address; Adolescent; Adult; Adverse drug event; Analgesics; Biological Assay; CYP2D6 gene; CYP3A4 gene; Cannabidiol; Cannabinoids; Cannabinol; Cannabis; Carboxylic Acids; Cells; Clinical; Clinical Trials; Cytochrome P450; Data; Development; Dose; Drug Interactions; Drug Kinetics; Enzymes; Exhibits; Future; Gene Frequency; Genetic Variation; Glucuronides; Glucuronosyltransferase; Goals; Human; Hydrocodone; Hydromorphone; Illicit Drugs; In Vitro; Individual; Knowledge; Lead; Liver Microsomes; Marijuana Smoking; Medical; Medical Marijuana; Metabolism; Minor; Modeling; Nature; Neurons; Opioid; Opioid agonist; Pain management; Parents; Pharmaceutical Preparations; Plasma; Population; Recombinants; Regimen; Research; Site-Directed Mutagenesis; System; Tetrahydrocannabinol; UGT2B7 UDP-glucuronosyltransferase; Variant; base; clinically relevant; demethylation; in vivo; marijuana legalization; marijuana use; mu opioid receptors; neurotransmitter release; opioid abuse; opioid epidemic; opioid use; pharmacokinetic model; physiologically based pharmacokinetics; prescription opioid; prescription opioid misuse

Abstract Opioids are commonly utilized in pain management therapies. Opioids are mu-opioid receptor (MOR) agonists that suppress excitatory neurotransmitter release, decrease overall excitability, and hyperpolarize neuronal cells, resulting in the desired analgesic effect. One of the most common opioids used is hydrocodone. Hydrocodone is primarily metabolized by cytochrome P450 (CYP) 3A4 and CYP2D6 through N-demethylation and O- demethylation to form its primary inactive metabolite, norhydrocodone, and an active metabolite, hydromorphone. Hydromorphone is further metabolized by UDP-glucuronosyltransferase (UGT) 2B7 through O- glucuronidation to its inactive metabolite hydromorphone-3-glucuronide. A growing concern over the past decade has been the opioid epidemic, where individuals are misusing prescription opioids including hydrocodone that are often used in combination with other illicit drugs, including cannabis. Our lab and previous studies have shown that major cannabinoids including Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN), and the THC metabolites 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC), and 11-nor-Δ9- tetrahydrocannabinol-carboxylic acid glucuronide (THC-COO-Gluc) inhibit several major drug metabolizing enzymes. Specifically, THC, 11-OH-THC, THC-COO-Gluc, and CBD inhibit CYP2D6, while THC, 11-OH-THC, and CBD inhibits CYP3A4. Our lab has also shown that THC, 11-OH-THC, THC-COO-Gluc, and CBD inhibit UGT2B7. We hypothesize that major cannabinoids and their metabolites will inhibit hydrocodone metabolism potentially leading to clinically relevant adverse drug-drug interactions (DDI) in individuals who use them concomitantly. The proposed study will examine the inhibitory effect of THC, CBD, CBN, 11-OH-THC, 11-COOH- THC, and THC-COO-Gluc against both wildtype (wt) and prevalent polymorphic variants involved in hydrocodone metabolism in vitro and examine the potential for DDI in vivo. The proposed research will identify the cannabinoids/cannabinoid metabolites that inhibit wt drug metabolizing enzymes (Aim 1) and their major polymorphic variants (Aim 2) that are involved in hydrocodone metabolism. The proposed research will also include a clinical trial investigating the potential DDI between cannabis and hydrocodone, with the pharmacokinetic data used to develop DDI models between hydrocodone and cannabis utilizing physiologically based pharmacokinetic (PBPK) modeling (Aim 3). These in vitro and in vivo studies will aid in evaluating the clinical relevance of the potential DDI between cannabis and hydrocodone in humans.

抽象的 阿片类药物通常用于疼痛管理疗法。阿片类药物是Mu-Apioid受体（MOR）激动剂 抑制兴奋性神经递质释放，降低总体兴奋性和超极化神经元细胞， 导致所需的镇痛作用。最常见的阿片类药物之一是氢可酮。 主要由细胞色素P450（CYP）3A4和CYP2D6代谢，通过N-甲基化和O- 脱甲基化以形成其主要的无活性代谢产物，非氢酮和活性代谢产物， 氢phone。液压电话由UDP-葡萄糖醛酸糖基转移酶（UGT）2B7进一步代谢 葡萄糖醛酸化与其无活跃的代谢产物液压液3-葡萄糖醛酸苷。在过去的十年中越来越关注 一直是阿片类药物的流行病，其中个体缺少处方阿片类药物，包括氢可酮， 我们通常与其他非法药物（包括大麻）结合使用。我们的实验室和以前的研究有 表明包括δ9-四氢大麻酚（THC），大麻二酚（CBD）和大麻醇在内的主要大麻素 （CBN）和THC代谢物11-羟基-Δ9-四氢大麻酚（11-OH-THC）和11-NOR-Δ9-- 四氢大麻醇 - 羧酸糖酰苷（THC-COO-GLUC）抑制几种主要药物代谢 酶。具体而言，THC，11-OH-THC，THC-COO-GLUC和CBD抑制CYP2D6，而THC，11-OH-THC， 和CBD抑制CYP3A4。我们的实验室还表明，THC，11-OH-THC，THC-COO-GLUC和CBD抑制 UGT2B7。我们假设主要的大麻素及其代谢物将抑制氢可酮代谢 可能导致使用临床相关的广告药物互动（DDI） 同时。拟议的研究将检查THC，CBD，CBN，11-OH-THC，11-COOH-的抑制作用 THC和THC-COO-GLUC针对野生型（WT）和参与的普遍多态性变体 体外氢可酮代谢，并检查了体内DDI的潜力。拟议的研究将确定 大麻素/大麻素代谢产物抑制WT药物代谢酶（AIM 1）及其主要 与氢可酮代谢有关的多态性变体（AIM 2）。拟议的研究也将 包括一项临床试验，研究大麻和氢可酮之间的潜在DDI，并与 用于开发氢可酮和大麻之间的DDI模型的药代动力学数据利用了物理 基于药代动力学（PBPK）建模（AIM 3）。这些体外和体内研究将有助于评估 人类大麻和氢可酮之间潜在DDI的临床相关性。