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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：
8501530
负责人：
Zeruesenay Desta
金额：
$ 35.47万
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/8501530
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.

描述（由申请人提供）：药物的有益和不良反应的个体差异会影响安全有效的治疗。这项研究的长期目标是了解导致这种变异性的机制。在当前资助期间，我们重点关注 CYP2B6 引起的药物处置和反应的变异性。这种肝酶代谢许多临床上重要的药物，但这些底物的临床用途因 CYP2B6 活性及其相关药物相互作用的广泛个体差异而受到影响。我们发现并验证了临床相关的新型底物、抑制剂和遗传标记，现在使 CYP2B6 临床研究成为可能。使用这些工具，我们证明CYP2B6遗传变异不仅影响底物代谢，而且深刻影响体外和体内药物相互作用的抑制程度。基因型和药物相互作用之间的相互作用在临床上很重要因为个体的基因型似乎会影响窄治疗范围 CYP2B6 底物（例如依非韦伦和美沙酮）所需的剂量调整，以避免不良反应。尽管取得了这些显着的进展，但 CYP2B6 活性的很大一部分个体间差异以及相关的药物相互作用仍然无法解释。在这一竞争性的更新中，我们将利用这些新颖且变革性的临床工具以及令人兴奋的新数据来全面阐明体内这种变异的机制。在目标 1 中，我们将检验以下假设：CYP2B6 中非同义 SNP 的作用是底物依赖性的，这反过来会影响药物相互作用。我们将在体外确定 CYP2B6*6 等位基因对一组底物和抑制剂的代谢动力学和抑制的影响。在目标 2 中，我们将确定 CYP2B6 遗传变异如何同时影响自抑制/自诱导并共同影响 CYP2B6 活性。将使用安非他酮作为基线探针（对照），在进行 CYP2B6*6 等位基因基因分型的健康志愿者中，使用单次 600 mg 口服剂量（抑制）和多次剂量（600 mg/天）依非韦伦（诱导和抑制）后测定体内酶活性。将开发一个半 PBPK 模型来预测每个因素的贡献以及这些因素之间的相互作用。在目标 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预测基础和药物诱导的 CYP2B6 活性。这种关联将使用我们提议的（目标 2）和之前完成的依非韦伦临床试验中的 DNA、血浆和尿液样本进行临床测试。我们的途径引导方法有望识别 CYP2B6 介导的药物清除和相互作用中个体差异的新型遗传生物标志物，并可以作为研究参与药物代谢的其他基因的范例。总的来说，我们将对 CYP2B6 活性可变及其底物代谢的机制有一个全面的了解，这些信息最终可用于个性化治疗。