Drug-drug interactions between cannabis and hydrocodone.

摘要 阿片类药物通常用于疼痛治疗。阿片类药物是单位阿片受体(MOR)激动剂 抑制兴奋性神经递质释放，降低整体兴奋性，并使神经细胞超极化， 从而达到预期的止痛效果。最常见的阿片类药物之一是氢可酮。氢可酮 主要由细胞色素P450(CYP)3A4和细胞色素P2D6通过N-去甲基化和O- 去甲基化以形成其主要的非活性代谢物去氢可酮和活性代谢物， 氢化吗啡。氢吗啡酮进一步被UDP-葡萄糖醛酸基转移酶(UGT)2B7通过O- 葡萄糖醛酸化为其非活性代谢物氢吗啉-3-葡萄糖醛酸苷。在过去的十年里，人们越来越担心 阿片类药物流行，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一起使用。我们的实验室和之前的研究已经 研究表明，主要的大麻类物质包括Δ-9-四氢大麻酚、大麻二酚和大麻酚 代谢物11-羟基-Δ-9-四氢大麻酚(11-OH-Δ9-THC)和11-Nor-Nor-THC 9- 四氢大麻酚-羧酸葡萄糖醛酸苷(THC-COO-Gluc)抑制几种主要药物的代谢 酵素。具体来说，THC、11-OH-THC、THC-COO-Gluc和CBD抑制CYP2D6，而THC、11-OH-THC、 CBD对细胞色素P3A4有抑制作用。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会抑制氢可酮的代谢。 可能导致临床相关的药物不良相互作用(DDI)的个人使用 随之而来的。拟议的研究将考察THC、CBD、CBN、11-OH-THC、11-COOH- THC和THC-COO-Gluc对野生型(Wt)和涉及到的流行的多态变体 氢可酮在体外的代谢，并检测DDI在体内的可能性。拟议的研究将确定 抑制药物代谢酶的大麻素/大麻素代谢物(目标1)及其主要 参与氢可酮代谢的多态变异体(AIM 2)。拟议的研究还将 包括一项临床试验，调查大麻和氢可酮之间潜在的DDI， 利用药代动力学数据建立氢可酮和大麻生理学上的DDI模型 基于药物动力学(PBPK)模型(目标3)。这些体外和体内研究将有助于评估 大麻和氢可酮之间潜在DDI在人类中的临床相关性。

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.