CYP2B6 Genetic Variations and Drug Interactions

CYP2B6 遗传变异和药物相互作用

基本信息

批准号：
8666765
负责人：
Zeruesenay Desta
金额：
$ 39.83万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-07 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8666765
关键词：
Address Adverse effects Affect Alleles Amino Acids Bupropion CYP2B6 gene Candidate Disease Gene Cells Clinical Clinical Research Clinical Trials Complex Cytochromes DNA Data Dose Drug Interactions Drug toxicity Enzyme Kinetics Enzymes Funding Genes Genetic Genetic Markers Genetic Polymorphism Genetic Variation Genotype Goals Health Care Costs Hepatic Human In Vitro Individual Kinetics Liver Microsomes Mediating Metabolism Methadone Mutation Nuclear Receptors Oral Pathway interactions Patients Pattern Persons Pharmaceutical Preparations Pharmacotherapy Phenotype Plasma Play Predisposition Process Proteins Public Health Regulatory Pathway Research Research Personnel Role Sampling Testing Therapeutic Toxic effect Urine Variant Voriconazole Xenobiotics base clinically relevant drug clearance drug metabolism efavirenz effective therapy enzyme activity experience genetic variant healthy volunteer improved in vitro activity in vivo inhibitor/antagonist non-genetic novel pharmacokinetic model protein expression public health relevance response tool

项目摘要

DESCRIPTION (provided by applicant): Interindividual variability in the beneficial and adverse effects of medications compromises safe and effective therapy. The long-term goal of this research is to understand the mechanisms that contribute to this variability. In the current funding period, we have focused on variability in drug disposition and response caused by CYP2B6. This hepatic enzyme metabolizes many clinically important drugs, but the clinical uses of these substrates are compromised by the extensive interindividual variability in CYP2B6 activity and its associated drug interactions. We discovered and validated clinically relevant novel substrate, inhibitors and genetic markers that now make CYP2B6 clinical research possible. Using these tools, we have demonstrated that CYP2B6 genetic variation not only affects substrate metabolism, but profoundly influences the degree of inhibition drug interactions in vitro and in vivo. This interplay between genotype and drug interactions is clinically important because an individual's genotype appears to affect dose adjustment needed for narrow therapeutic range CYP2B6 substrates (e.g., efavirenz and methadone) to avoid adverse effects. Despite these notable advances, the large portion of interindividual variability in CYP2B6 activity and associated drug interactions remains unexplained. In this competing renewal, we will capitalize on these novel and transformative clinical tools as well as exciting new data to comprehensively elucidate the mechanisms responsible for this variability in vivo. In Aim 1, we will test the hypothesis that the effect of nonsynonomous SNPs in CYP2B6 are substrate dependent and this, in turn, affects drug interactions. We will determine the influence of the CYP2B6*6 allele on kinetics of metabolism and inhibition of a panel of substrates and inhibitors in vitro. In Aim 2, we will determine how CYP2B6 genetic variants affect simultaneous auto- inhibition/autoinduction and collectively influence CYP2B6 activity. In vivo enzyme activity will be determined using bupropion as a probe at baseline (control), with a single 600 mg oral dose (inhibition) and after multiple doses (600 mg/day) (induction and inhibition) of efavirenz in healthy volunteers genotyped for CYP2B6*6 allele. A semi-PBPK model will be developed to predict the contribution each and interplay among these factors. In Aim 3, we will the test the hypothesis that genetic variants in genes that regulate CYP2B6 expression and function predict basal and drug-induced CYP2B6 activity. This association will be tested clinically using DNA, plasma and urine samples from our proposed (Aim 2) and previously completed efavirenz clinical trials. Our pathway-guided approach is expected to identify novel genetic biomarkers of interindividual variability in CYP2B6-mediated drug clearance and interactions, and may serve as a paradigm for studying other genes involved in drug metabolism. Overall, we will develop a comprehensive understanding of mechanisms responsible for variable CYP2B6 activity and the metabolism of its substrates, and this information could be eventually used to personalize therapy. PUBLIC HEALTH RELEVANCE: Some patients receive little or no clinical benefit from drugs and others may experience drug interactions and toxicity, with a huge toll in lives and public health costs. A person's genetic makeup can affect drug disposition and effects, as well as the susceptibility to drug interactions. The goal of this project is to improve understanding of the effect of these genetic changes on drug disposition and drug interactions, and use this information to avoid toxicity and maximizing benefit.

描述（由申请人提供）：药物的有益和不利影响的个体变异性会损害安全有效的治疗。这项研究的长期目标是了解导致这种变异性的机制。在当前的资金期间，我们专注于CYP2B6引起的药物处置和反应的变异性。这种肝酶代表了许多临床上重要的药物，但是这些底物的临床用途因CYP2B6活性的广泛个体差异及其相关的药物相互作用而受到损害。我们发现并验证了与临床相关的新型底物，抑制剂和遗传标志物，这些标志物现在使CYP2B6临床研究成为可能。使用这些工具，我们已经证明CYP2B6遗传变异不仅影响底物代谢，而且深刻影响了体外和体内抑制药物相互作用的程度。基因型与药物相互作用之间的这种相互作用在临床上很重要因为一个人的基因型似乎会影响狭窄的治疗范围CYP2B6底物（例如Efavirenz和美沙酮）所需的剂量调整，以避免不良反应。尽管有这些显着的进步，但CYP2B6活动中个体间的大部分变异性很大并且相关的药物相互作用仍无法解释。在这种竞争的续约中，我们将利用这些新颖的变革性临床工具以及令人兴奋的新数据，以全面阐明导致这种变异性的机制。在AIM 1中，我们将检验以下假设：CYP2B6中非语言SNP的作用是底物依赖性，这反过来影响药物相互作用。我们将确定CYP2B6*6等位基因对代谢动力学的影响以及在体外抑制底物和抑制剂的影响。在AIM 2中，我们将确定CYP2B6遗传变异如何影响同时自动抑制/自动诱导并统一影响CYP2B6活性。体内酶的活性将使用安非他酮作为基线（对照）的探针确定，单个600 mg口服剂量（抑制）和多剂量（600 mg/day）（600 mg/day）（诱导和抑制）Efavirenz的健康志愿者在CYP2B6*6*6等位基因中均具有基因型。将开发一个半PBPK模型，以预测这些因素之间的贡献和相互作用。在AIM 3中，我们将检验以下假设：调节CYP2B6表达和功能的基因中的遗传变异可以预测基础和药物诱导的CYP2B6活性。该关联将使用我们提出的DNA，血浆和尿液样品（AIM 2）和先前完成的Efavirenz临床试验进行临床测试。我们的途径引导的方法有望确定CYP2B6介导的药物清除和相互作用中个体变异性的新型遗传生物标志物，并可以作为研究其他涉及药物代谢的基因的范例。总体而言，我们将对负责可变CYP2B6活性及其底物代谢的机制进行全面的理解，并最终可以将这些信息用于个性化治疗。公共卫生相关性：有些患者从药物中几乎没有或根本没有临床利益，而其他患者可能会遇到药物相互作用和毒性，而生活和公共卫生成本却巨大。一个人的遗传构成会影响药物处置和作用，以及对药物相互作用的敏感性。该项目的目的是提高对这些遗传变化对药物处置和药物相互作用的影响的理解，并使用此信息来避免毒性和最大程度地提高利益。