CYP2B6 genetic variations and drug interactions

CYP2B6 遗传变异和药物相互作用

• 批准号: 8077814
• 负责人: Zeruesenay Desta
• 金额: $ 12.97万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8077814
• 关键词: Affect; Aftercare; Alleles; Area; CYP2B6 gene; Clinical; Clinical Research; Clinical Trials; Complex; Cytochrome P450; 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; improved; in vivo; inhibitor/antagonist; novel; pharmacokinetic model; programs; response

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）：由于患者对药物反应的巨大差异，使得合理的药物治疗变得困难，并且药物清除和药物相互作用的遗传差异也导致了这一点。该建议旨在通过研究细胞色素P450 (CYP) 2B6，提高我们对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是一种研究较少的酶，但它在许多临床重要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基因变异不仅影响对许多药物的清除和反应，还影响药物相互作用过程中CYP2B6的相对易感性。PI实验室的研究已经确定了CYP2B6活性的特异性探针（efavirenz）和定义标签snp （G516T和A785G）的最常见和功能重要的变异等位基因（CYP2B6*6）。本文概述了CYP2B6*6等位基因对依非韦伦代谢和药物相互作用影响的体外和临床研究。在目标一中，我们将测试CYP2B6*6等位基因影响CYP2B6基线活性并改变体外抑制反应的假设。将在CYP2B6*6等位基因分型的人肝脏微粒体中测定依非韦伦的代谢和对抑制剂的易感性。在目标二中，我们将通过测量依非韦伦（100mg单次口服剂量）的代谢来验证CYP2B6*6等位基因在体内影响CYP2B6活性的假设。在第三个目标中，我们将验证CYP2B6*6等位基因影响体内对抑制性药物相互作用的反应性的假设。将在CYP2B6*6等位基因分型的健康志愿者中测定伏立康唑（PI新发现的抑制剂）对依非韦伦（100 mg单剂量）药代动力学的影响。在目标四中，我们将检验CYP2B6*6等位基因影响药物稳态暴露的假设，这些药物会经历其代谢的“自我诱导”，从而影响与它们相关的药物相互作用。1)在CYP2B6*6等位基因分型的健康志愿者中测定依非韦伦单剂量和多剂量药代动力学；2)在多次给药efavirenz前后评估所选CYPs的活性。总之，这些研究将为通过优化有益效果和避免药物不良反应来改善CYP2B6代谢药物的治疗奠定基础。