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：
8077245
负责人：
Zeruesenay Desta
金额：
$ 27.28万
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 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8077245
关键词：
Affect Aftercare Alleles Area CYP2B6 gene Clinical Clinical Research Clinical Trials Complex Cytochromes Data Dose Drug Exposure Drug Interactions Drug Kinetics Enzymes Future Genes Genetic Genetic Variation Genotype Goals Haplotypes Human In Vitro Inherited Kinetics Laboratories Liver Measures Metabolic Metabolism Microsomes Modeling Oral Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Plasma Play Predisposition Process Protein Isoforms Reaction Relative (related person)Research Personnel Role System Testing Time Tissues Toxic Environmental Substances Urine Variant Voriconazole Weight activity marker base clinically relevant drug clearance drug metabolism efavirenz genetic inhibitor genetic variant healthy volunteer human CYP2B6 protein improved in vivo inhibitor/antagonist novel pharmacokinetic model programs response

项目摘要

DESCRIPTION (provided by applicant): Rational drug therapy is made difficult by large interpatient variability in response to drugs, and inherited differences in drug clearance and drug interactions contribute to this. This proposal is directed at improving our understanding of mechanisms of variable drug response based on genetics and drug interactions through the study of cytochrome P450 (CYP) 2B6. CYP2B6 is an enzyme that has been studied less than other CYPs, but one that plays a central role in the metabolism of many clinically important drugs and the drug interactions that ensue. We hypothesize that CYP2B6 genetic variations influence not only the clearance of and response to many drugs but also the relative susceptibility of CYP2B6 during drug-drug interactions. Studies in the PI's laboratory have identified a specific probe of CYP2B6 activity (efavirenz) and the most common and functionally important variant allele (CYP2B6*6) defining tagSNPs (G516T and A785G). In vitro and clinical studies are outlined in this proposal to test the influence of CYP2B6*6 allele on efavirenz metabolism and drug interactions. In aim one, we will test the hypothesis that the CYP2B6*6 allele influences baseline CYP2B6 activity and alters response to inhibition in vitro. Efavirenz metabolism and susceptibility to inhibitors will be determined in microsomes from human livers genotyped for the CYP2B6*6 allele. In aim two, we will test the hypothesis that the CYP2B6*6 allele influences CYP2B6 activity in vivo by measuring the metabolism of efavirenz (100 mg single oral dose). In aim three, we will test the hypothesis that the CYP2B6*6 allele influences responsiveness to inhibitory drug interactions in vivo. The effect of voriconazole (a newly identified inhibitor by the PI) on efavirenz (100 mg single dose) pharmacokinetics will be determined in healthy volunteers genotyped for the CYP2B6*6 allele. In aim four, we will test the hypothesis that the CYP2B6*6 allele influences steady-state exposure of drugs that undergo "autoinduction" of their metabolism, and thereby the drug interactions associated with them. 1) Single- and multiple- dose pharmacokinetics of efavirenz will be determined in healthy volunteers genotyped for the CYP2B6*6 allele; 2) the activity of selected CYPs will be assessed before and after multiple doses of efavirenz. Together, these studies will lay the groundwork for improved therapy with a growing list of drugs that are metabolized by CYP2B6 through optimizing beneficial effects and avoiding adverse drug reactions.

描述（由申请人提供）：响应药物的大室内变异性使合理的药物治疗难以使药物清除和药物相互作用的继承差异有助于这一点。该建议旨在通过研究细胞色素P450（CYP）2B6来改善我们基于遗传学和药物相互作用的可变药物反应机制的理解。 CYP2B6是一种比其他CYP少的酶，但是在许多临床上重要的药物的代谢和随之而来的药物相互作用中起着核心作用。我们假设CYP2B6遗传变异不仅会影响对许多药物的清除和反应，而且会影响CYP2B6在药物相互作用过程中的相对敏感性。 PI实验室的研究确定了CYP2B6活性（Efavirenz）的特定探针以及最常见且功能上重要的变体等位基因（CYP2B6*6）定义TAGSNPS（G516T和A785G）。该提案中概述了体外和临床研究，以测试CYP2B6*6等位基因对Efavirenz代谢和药物相互作用的影响。在目标中，我们将检验以下假设：CYP2B6*6等位基因影响基线CYP2B6活性并改变对体外抑制的反应。 Efavirenz代谢和对抑制剂的敏感性将在来自CYP2B6*6等位基因的人肝基因分型的微粒体中确定。在目标二中，我们将通过测量Efavirenz（100 mg单口服剂量）的代谢来测试CYP2B6*6等位基因在体内影响CYP2B6活性的假设。在目标三中，我们将检验以下假设：CYP2B6*6等位基因影响体内抑制性药物相互作用的反应性。将在针对CYP2B6*6等位基因的健康志愿者基因型中确定伏立康唑（由PI新鉴定的抑制剂）对Efavirenz（100 mg单剂量）药代动力学的影响。在AIM四，我们将检验以下假设：CYP2B6*6等位基因会影响经历其代谢“自动诱导”的药物的稳态暴露，从而与它们相关的药物相互作用。 1）Efavirenz的单剂量药代动力学将在CYP2B6*6等位基因的健康志愿者基因型中确定； 2）选定的CYP的活性将在多剂量的efavirenz之前和之后评估。总之，这些研究将通过越来越多的药物列表来改善治疗的基础，这些药物通过优化有益作用并避免不良药物反应而被CYP2B6代谢。