Variable brain oxycodone metabolism alters drug effect

可变的脑羟考酮代谢改变药物作用

• 批准号: 9789231
• 负责人: RACHEL Fynvola TYNDALE
• 金额: $ 30.63万
• 依托单位: UNIVERSITY OF TORONTO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789231
• 关键词: Absence of pain sensation; Affect; Analgesics; Animals; Blood; Brain; CYP3A4 gene; Cerebral Ventricles; Chemicals; Chronic; Codeine; Consumption; Crime; Cytochrome P450; Data; Dependence; Dopamine; Dopamine Receptor; Dose; Drug Addiction; Drug Kinetics; Drug Modelings; Emergency department visit; Enzymes; Foundations; Gender; Genetic; Health Care Costs; Hepatic; Human; Hydrocodone; Individual; Knowledge; Lead; Liver; Measures; Metabolic; Metabolic Activation; Metabolism; Methods; Microdialysis; Modeling; Morphine; Neurotransmitters; Nicotine; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Receptor; Opioid agonist; Opioid user; Oral; Oxycodone; Oxymorphone; Pain management; Parents; Pharmaceutical Preparations; Plasma; Play; Positron-Emission Tomography; Productivity; Rattus; Reporting; Research Methodology; Rewards; Risk; Role; Sex Differences; Smoker; Smoking; Source; Techniques; Testing; Time; Tramadol; Treatment Failure; Variant; Woman; addiction; brain metabolism; brain pathway; drug misuse; drug reward; environmental chemical; experience; high reward; high risk; human model; imaging study; improved; inhibitor/antagonist; inter-individual variation; liver function; mu opioid receptors; nicotine patch; non-smoker; novel; opiate tolerance; opioid abuse; opioid exposure; overdose death; pain relief; pharmacodynamic model; pharmacokinetic model; preclinical study; preference; receptor binding; response; sex; societal costs; translational study; virtual

7. Project Summary/Abstract Opioid drugs are effective pain-relievers that elicit analgesia through their action at brain µ-opioid receptors, simultaneously activating rewarding brain pathways, which can lead to opioid tolerance and drug dependence. The U.S. has the highest world-wide per capita use of opioids creating enormous health and societal costs related to addiction and treatment, lost productivity, and increased crime. Response to opioid drugs varies widely between people, and potentially between genders, but it is not clear why people experience different levels of pain relief from the same opioid, and why some people progress to become addicted. Many opioids are activated to even more potent µ-opioid receptor agonists by CYP2D enzymes, such as oxycodone that is converted to oxymorphone. However, oxymorphone is transported out of the brain and body more rapidly than oxycodone, hence oxycodone is responsible for analgesia. This project uses unique research methods to investigate how metabolism of opioids by CYP2D enzymes in the brain is important in oxycodone, tramadol and hydrocodone response. Both liver and brain CYP2D levels are regulated by genetics, but in addition, brain CYP2D is very sensitive to environmental chemicals, notably nicotine. Therefore, there can be two individuals who have the same CYP2D activity in the liver (same genetics) but very different levels of CYP2D activity in the brain, e.g. through smoking. Their drug and metabolite blood levels may be similar, but metabolism by brain CYP2D can alter oxycodone levels in the brain, influencing pain relief, tolerance and abuse liability. “How does variation in oxycodone metabolism by CYP2D in the brain affect oxycodone analgesia and reward?” Validated rat models of analgesia, tolerance and reward, will be used with drug and dopamine microdialysis, pharmacokinetic modelling, and established methods of manipulating brain but not liver CYP2D levels. Brain CYP2D will be reduced by injecting chemical inhibitors into the brain, and increased by chronic systemic nicotine treatment. Decreased brain CYP2D should increase analgesia, tolerance and reward through reduced oxycodone conversion to oxymorphone, resulting in higher brain oxycodone levels. Increased brain CYP2D should decrease analgesia, tolerance and reward through greater metabolism of oxycodone to oxymorphone, resulting in lower brain oxycodone levels. Plasma oxycodone and metabolites levels will not change as liver CYP2D is unaffected by these manipulations. Two additional CYP2D substrates, the commonly prescribed oral opioids, hydrocodone and tramadol, and sex differences in oxycodone responses will also be investigated. This will improve mechanistic understanding of this novel source of variation between people in their opioid response, and identification of individuals at risk for opioid pain-treatment failure and progression to dependence on these widely used oral opioids. Extensive PB-PK modelling will assist in extrapolations to human, as will planned human PET imaging studies. The knowledge acquired from this project will contribute to our on-going efforts to reduce the societal and health costs of opioid drug misuse and dependence.

7.项目摘要/摘要 阿片类药物是有效的止痛药，通过作用于大脑中的阿片受体而产生镇痛作用。 同时激活奖励大脑通路，这可能导致阿片类药物耐受和药物依赖。 美国是世界上人均阿片类药物使用量最高的国家，这造成了巨大的健康和社会成本 与上瘾和治疗、生产力下降和犯罪率增加有关。对阿片类药物的反应各不相同 人与人之间的差异很大，可能在性别之间也是如此，但尚不清楚为什么人们会有不同的体验 同样的阿片类药物缓解疼痛的程度，以及为什么有些人会逐渐上瘾。许多阿片类药物 被更有效的微阿片受体激动剂激活，如羟考酮 改成了羟吗啡酮。然而，羟吗啡酮从大脑和身体中运输出来的速度比 羟考酮，因此羟考酮负责止痛。这个项目使用了独特的研究方法 研究在羟考酮、曲马多中，脑内细胞色素P450酶对阿片类药物代谢的重要性 氢可酮反应。肝脏和大脑的CYP2D水平都受基因调节，但除此之外，大脑 CYP2D对环境化学物质非常敏感，尤其是尼古丁。因此，可以有两个人 在肝脏中具有相同的CYP2D活性(相同的基因)，但在 大脑，例如通过吸烟。他们的药物和代谢产物的血液水平可能是相似的，但新陈代谢是通过 大脑中的CYP2D可以改变大脑中的羟考酮水平，影响疼痛缓解、耐受性和滥用倾向。 “脑组织中羟考酮代谢的变化如何影响羟考酮的镇痛作用？” 奖赏？“经过验证的大鼠止痛、耐受和奖励模型将与药物和多巴胺一起使用 微透析、药代动力学模型和已建立的脑而不是肝细胞色素P450-2D的操作方法 级别。脑内注射化学抑制剂会减少大脑中的细胞色素P450 2 D，而慢性药物会增加大脑中的细胞色素P450 2 D 全身尼古丁治疗。脑内细胞色素P450-2D的减少应通过增加镇痛、耐受性和奖赏 羟考酮转化为羟考酮减少，导致脑羟考酮水平升高。脑容量增加 通过羟考酮的更大代谢来减少疼痛、耐受性和奖赏 羟考酮，导致大脑羟考酮水平较低。血浆羟考酮和代谢物水平不会 改变，因为肝脏的CYP2D不受这些操作的影响。两种额外的CYP2D底物，通常 处方阿片类药物、氢可酮和曲马多，以及羟考酮反应的性别差异也将 调查过了。这将提高对人与人之间这种新的差异来源的机械性理解 他们的阿片类药物反应，以及识别有阿片类疼痛治疗失败和进展到 对这些广泛使用的口服阿片类药物的依赖。广泛的PB-PK建模将有助于外推 人类，就像计划中的人类PET成像研究一样。从这个项目中获得的知识将有助于 感谢我们为减少阿片类药物滥用和依赖造成的社会和健康成本所作的持续努力。