Impact CYP2D6 Phenotype on Response to Methamphetamine in Humans

CYP2D6 表型对人类甲基苯丙胺反应的影响

• 批准号: 8299351
• 负责人: Alison Oliveto
• 金额: $ 17.51万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299351
• 关键词: African American; Ataxia; Behavioral; Belief; Caffeine; Cardiovascular system; Caucasians; Caucasoid Race; Clinical Trials; Cocaine Dependence; Codeine; Cognitive Therapy; Cytochrome P-450 CYP2D6; Data; Dependence; Development; Disease; Dose; Drug Addiction; Drug Kinetics; Economics; Employee Strikes; Ensure; Enzymes; Future; Genes; Genetic; Genetic Polymorphism; Genotype; High Prevalence; Human; Impaired cognition; Intervention; Japanese Population; Legal; Measures; Mediating; Medical; Metabolic; Metabolism; Methamphetamine; Methamphetamine dependence; Modeling; Morphine; Nicotine; Opioid; Opioid Analgesics; Outcome; Participant; Pathway interactions; Patient Self-Report; Performance; Pharmaceutical Preparations; Pharmacodynamics; Phenotype; Placebos; Prevalence; Prevention; Prodrugs; Reaction Time; Recovery; Relative (related person); Reporting; Research; Risk; Role; Serum; Severities; System; Testing; Time; Toxic effect; Treatment outcome; United States; Work; aged; behavior test; clinically relevant; contingency management; drug of abuse; genetic variant; healthy volunteer; novel; preference; primary outcome; psychosocial; response; secondary outcome; social; success; urinary

DESCRIPTION (provided by applicant): Methamphetamine (METH) dependence is prevalent in several regions of the US and has serious medical and social consequences. Several psychosocial interventions have shown moderate efficacy while no medication has shown robust efficacy for treating this disorder to date. Thus, novel medications development strategies for treating METH dependence are needed. Genetically mediated metabolic factors have been shown to impact vulnerability for drug dependence, with extensive metabolizers (EMs) typically demonstrating a greater risk for and severity of dependence on drugs such as nicotine and certain opioid analgesics than poor metabolizers (PMs). METH is initially metabolized via the cytochrome P450 2D6 (CYP2D6) enzyme system, which has several clinically relevant genetic variants; however, to our knowledge, the impact of this metabolic factor on the abuse liability of METH has not been extensively examined. A recent study showed that there was a significantly higher prevalence of EMs than PMs in Japanese participants who were METH dependent relative to those who were not. In addition, the prevalence of METH use is much lower among African Americans than Caucasians. Although reasons for this difference may include limited access to the drug and social beliefs, genetics could contribute to these racial divergences, in that African Americans have double the prevalence of PMs with CYP2D6. Thus, we hypothesize that genetically mediated metabolic factors modify METH preference and that pathways identified through genetic differences may provide effective pharmacological targets for medications development efforts. The specific aims of this project are to 1) determine the interaction between CYP2D6 phenotype and response to METH; 2) determine the role of CYP2D6 in behavioral/pharmacokinetic response to METH by testing the behavioral effects of agents that serve as positive (codeine) and negative (caffeine) controls for CYP2D6 phenotype. To this end, 20 healthy volunteers (aged 18-50) will be stratified by CYP2D6 phenotype after undergoing an 8-hr debrisoquine urinary recovery ratio test, and undergo five sessions in which METH (10 mg/70 kg, P.O. and either 5 or 15 mg/70 kg, PO), caffeine (500 mg/70 kg), codeine (120 mg/70 kg) or placebo is administered in random order. During each experimental session, the following measures will be assessed: 1) self-reported positive and negative subjective effects; 2) performance effects, as measured by reaction time, coordination, and cognitive impairment; 3) cardiovascular effects, as a measure of toxicity; and 4) pharmacokinetic profile, as measured by serum levels of drug and drug metabolite over time. These measures will provide a wide profile of effects to determine whether any effects are impacted by phenotype. These results will identify whether metabolic factors impact the response to METH as they do for other classes of drugs, provide preliminary data for larger clinical trials examining the interaction between genetic factors mediating both pharmacokinetic and pharmacodynamic effects of METH, and potentially guide novel medications development strategies for treating METH dependence. PUBLIC HEALTH RELEVANCE: Methamphetamine (METH) dependence has serious medical and social consequences, but no treatments have had complete success thus far. This study will examine whether metabolic phenotype impacts behavioral response to METH. Results of this study may uncover genetically determined metabolic factors that may increase or decrease abuse liability of METH, thereby providing new directions for prevention and treatment for METH dependence.

描述(申请人提供)：甲基苯丙胺(冰毒)依赖在美国的几个地区很普遍，并具有严重的医学和社会后果。几种心理社会干预措施已经显示出中等的疗效，而到目前为止，还没有药物显示出治疗这种疾病的强大疗效。因此，需要新的药物开发策略来治疗冰毒依赖。基因介导的代谢因素已被证明影响药物依赖的易感性，广泛代谢物(EM)通常比低代谢物(PM)对尼古丁和某些阿片类止痛剂等药物的依赖风险和严重性更大。冰毒最初是通过细胞色素P450 2D6(细胞色素P450 2D6)酶系统代谢的，该系统有几个临床相关的遗传变异；然而，据我们所知，这种代谢因素对冰毒滥用倾向的影响尚未被广泛研究。最近的一项研究表明，与不依赖冰毒的人相比，有冰毒依赖的日本参与者的EMS患病率明显高于PMS。此外，非裔美国人的冰毒使用率远低于高加索人。尽管造成这种差异的原因可能包括获得药物的机会有限和社会信仰，但遗传因素可能是导致这些种族差异的原因之一，因为非裔美国人患PMS的比例是携带CYP2D6的人的两倍。因此，我们假设基因介导的代谢因素改变了冰毒偏好，通过遗传差异确定的途径可能为药物开发努力提供有效的药理学靶点。本项目的具体目标是：1)确定CYP2D6表型与冰毒反应之间的相互作用；2)通过测试作为阳性(可待因)和阴性(咖啡因)对照的药物的行为效应，确定CYP2D6在冰毒的行为/药代动力学反应中的作用。为此，20名健康志愿者(年龄18-50岁)将在接受8小时尿回收率测试后按CYP2D6表型分层，并接受5次甲氨蝶呤(10 mg/70 kg，P.O.和5或15 mg/70 kg，PO)、咖啡因(500 mg/70 kg)、可待因(120 mg/70 kg)或安慰剂的5次治疗。在每一次实验期间，将评估以下措施：1)自我报告的积极和消极的主观影响；2)绩效影响，以反应时间、协调性和认知障碍衡量；3)心血管影响，作为毒性的衡量标准；以及4)药代动力学特征，以血清药物和药物代谢物水平随时间的推移衡量。这些措施将提供广泛的影响范围，以确定任何影响是否受表型的影响。这些结果将确定代谢因素是否像对其他类别的药物一样影响对冰毒的反应，为更大规模的临床试验提供初步数据，以检验介导冰毒药代动力学和药效学效应的遗传因素之间的相互作用，并有可能指导治疗冰毒依赖的新药物开发策略。 与公共卫生相关：甲基苯丙胺(冰毒)依赖会造成严重的医疗和社会后果，但到目前为止还没有一种治疗方法取得完全成功。这项研究将检验代谢表型是否影响冰毒的行为反应。这项研究的结果可能揭示可能增加或减少冰毒滥用倾向的遗传决定的代谢因素，从而为冰毒依赖的预防和治疗提供新的方向。