Impact CYP2D6 Phenotype on Response to Methamphetamine in Humans

描述（由申请人提供）：甲基苯丙胺（METH）依赖在美国的几个地区普遍存在，并具有严重的医疗和社会后果。一些心理社会干预措施显示出中等疗效，而迄今为止，没有药物显示出治疗这种疾病的强大疗效。因此，需要用于治疗METH依赖的新型药物开发策略。遗传介导的代谢因素已被证明会影响药物依赖的脆弱性，与弱代谢者（PM）相比，强代谢者（EM）通常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。METH最初通过细胞色素P450 2D 6（CYP 2D 6）酶系统代谢，该酶系统具有几种临床相关的遗传变异;然而，据我们所知，尚未广泛研究该代谢因素对METH滥用倾向的影响。最近的一项研究表明，有一个显着更高的发病率EM比PM在日本参与者谁是METH依赖相对于那些谁不是。此外，非裔美国人使用METH的流行率远低于白人。虽然造成这种差异的原因可能包括有限的药物和社会信仰，遗传学可能有助于这些种族差异，因为非洲裔美国人有两倍的患病率与CYP 2D 6 PM。因此，我们假设，遗传介导的代谢因素修改METH的偏好，通过遗传差异识别的途径可能为药物开发工作提供有效的药理学靶点。本项目的具体目的是：1）确定CYP 2D 6表型与对METH的反应之间的相互作用; 2）通过检测作为CYP 2D 6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CYP 2D 6在对METH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）将在经历8小时异喹胍尿回收率测试后按CYP 2D 6表型分层，并经历五个阶段，其中METH（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）或安慰剂以随机顺序给药。在每个实验阶段期间，将评估以下指标：1）自我报告的积极和消极主观效应; 2）表现效应，如通过反应时间、协调和认知障碍测量的; 3）心血管效应，作为毒性的量度;和4）药代动力学特征，如通过药物和药物代谢物随时间的血清水平测量的。这些指标将提供广泛的效应特征，以确定任何效应是否受表型影响。这些结果将确定代谢因素是否会影响对METH的反应，就像对其他类型药物一样，为更大规模的临床试验提供初步数据，研究介导METH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METH依赖的新药开发策略。

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.