Impact CYP2D6 Phenotype on Response to Methamphetamine in Humans

描述（由申请人提供）：甲基苯丙胺（冰毒）依赖在美国几个地区普遍存在，并具有严重的医疗和社会后果。一些社会心理干预措施已显示出中等疗效，但迄今为止没有任何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。遗传介导的代谢因素已被证明会影响药物依赖的易感性，广泛代谢物（EMs）通常比低代谢物（pm）表现出对尼古丁和某些阿片类镇痛药等药物依赖的更大风险和严重程度。甲基苯丙胺最初通过细胞色素P450 2D6 （CYP2D6）酶系统代谢，该系统具有几种临床相关的遗传变异；然而，据我们所知，这种代谢因素对甲基苯丙胺滥用的影响尚未得到广泛研究。最近的一项研究表明，在依赖冰毒的日本参与者中，与不依赖冰毒的参与者相比，EMs的患病率明显高于pm。此外，非裔美国人使用冰毒的比例远低于白种人。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，但遗传可能导致这些种族差异，因为非裔美国人CYP2D6的经前综合症患病率是非裔美国人的两倍。因此，我们假设遗传介导的代谢因素改变了甲基苯丙胺的偏好，并且通过遗传差异确定的途径可能为药物开发工作提供有效的药理学靶点。该项目的具体目标是：1)确定CYP2D6表型与甲基安非他明反应之间的相互作用；2)通过检测作为CYP2D6表型阳性（可待因）和阴性（咖啡因）对照的药物的行为效应，确定CYP2D6在甲基苯丙胺行为/药代动力学反应中的作用。为此，20名健康志愿者（18-50岁）在接受8小时的碎片喹尿恢复率测试后，将根据CYP2D6表型进行分层，并进行5次治疗，其中甲基苯丙胺（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）或安慰剂随机给药。在每个实验阶段，将评估以下措施：1)自我报告的积极和消极主观影响；2)表现效应，通过反应时间、协调性和认知障碍来衡量；3)心血管效应，作为毒性的衡量标准；4)药代动力学特征，通过血清药物水平和药物代谢物随时间的变化来测量。这些措施将提供广泛的影响概况，以确定是否有任何影响受到表型的影响。这些结果将确定代谢因素是否会影响对甲基苯丙胺的反应，就像它们对其他类别的药物一样，为更大规模的临床试验提供初步数据，研究介导甲基苯丙胺药代动力学和药效学效应的遗传因素之间的相互作用，并可能指导治疗甲基苯丙胺依赖的新药物开发策略。

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.