Drug-drug interactions between cannabis and hydrocodone.

摘要 阿片类药物通常用于疼痛管理治疗。阿片类药物是μ阿片受体（莫尔）激动剂 其抑制兴奋性神经递质释放、降低总体兴奋性和过度兴奋神经元细胞， 从而产生所需的镇痛效果。最常用的阿片类药物之一是氢可酮。氢可待因 主要由细胞色素P450（CYP）3A 4和CYP 2D 6通过N-去甲基化和O- 去甲基化以形成其主要非活性代谢物去甲氢可酮和活性代谢物， 氢吗啡酮氢吗啡酮通过UDP-葡萄糖醛酸基转移酶（UGT）2B 7通过O- 葡萄糖醛酸化为无活性代谢物氢吗啡酮-3-葡萄糖醛酸苷。在过去的十年里， 阿片类药物的流行，个人滥用处方阿片类药物，包括氢可酮， 经常与包括大麻在内的其他非法药物结合使用。我们的实验室和以前的研究 表明主要大麻素包括Δ9-四氢大麻酚（THC）、大麻二酚（CBD）和大麻酚 (CBN)和THC代谢物11-羟基-Δ9-四氢大麻酚（11-OH-THC）和11-去甲-Δ9- 四氢大麻酚羧酸葡糖苷酸（THC-COO-Gluc）抑制几种主要药物代谢 内切酶具体而言，THC、11-OH-THC、THC-COO-Gluc和CBD抑制CYP 2D 6，而THC、11-OH-THC、 CBD抑制CYP 3A 4。我们的实验室还表明，THC，11-OH-THC，THC-COO-Gluc和CBD抑制 UGT 2B7。我们假设主要的大麻素及其代谢产物会抑制氢可酮的代谢 在使用它们的个体中可能导致临床相关的药物不良相互作用（DDI） 伴随着。该研究将检测THC、CBD、CBN、11-OH-THC、11-COOH- THC和THC-COO-Gluc针对野生型（wt）和涉及以下的普遍多态性变体： 氢可酮的体外代谢和体内DDI的潜力。拟议的研究将确定 抑制野生型药物代谢酶（Aim 1）的大麻素/大麻素代谢物和它们的主要 多态性变体（Aim 2）参与氢可酮代谢。拟议的研究还将 包括一项调查大麻和氢可酮之间潜在DDI的临床试验， 用于开发氢可酮和大麻之间DDI模型的药代动力学数据， 基于药代动力学（PBPK）建模（目的3）。这些体外和体内研究将有助于评估 大麻和氢可酮在人体内潜在DDI的临床相关性。

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.