CYP2B6 genetic variations and drug interactions

CYP2B6 遗传变异和药物相互作用

• 批准号: 7258579
• 负责人: Zeruesenay Desta
• 金额: $ 26.47万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 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/7258579
• 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; End Point; 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; base; clinically relevant; day; 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)：合理的药物治疗由于患者之间对药物反应的巨大差异而变得困难，药物清除和药物相互作用的遗传差异导致了这一点。这一建议旨在通过对细胞色素P450(CYP)2B6的研究，从遗传学和药物相互作用的角度来提高我们对可变药物反应机制的理解。CYP2B6是一种研究较少的酶，但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发挥着核心作用。我们推测，在药物相互作用过程中，CYP2B6基因变异不仅影响许多药物的清除和反应，而且还影响其相对易感性。PI实验室的研究已经确定了CYP2B6活性的特定探针(Efavirenz)和定义标签SNPs(G516T和A785G)的最常见和最重要的变异等位基因(CYP2B6*6)。这项建议概述了体外和临床研究，以测试CYP2B6*6等位基因对Eefavirenz代谢和药物相互作用的影响。在第一个目标中，我们将在体外验证这一假设，即CYP2B6*6等位基因影响基线的CYP2B6活性并改变对抑制的反应。将在人类肝脏的微生物体中确定CYP2B6*6等位基因的基因分型，以确定Eefavirenz的代谢和对抑制剂的敏感性。在第二个目标中，我们将通过测量单次口服100 mg的依法韦仑的代谢来验证CYP2B6*6等位基因影响体内CYP2B6活性的假说。在第三个目标中，我们将检验这一假说，即CYP2B6*6等位基因在体内影响对抑制药物相互作用的反应性。伏立康唑(PI新近发现的一种抑制剂)对健康志愿者的药物动力学的影响将在健康志愿者中确定，这些志愿者的等位基因为CYP2B6*6。在第四个目标中，我们将检验这样一个假设，即CYP2B6*6等位基因影响药物的稳态暴露，这些药物经历了代谢的“自动诱导”，从而影响了与它们相关的药物相互作用。1)将在携带CYP2B6*6等位基因的健康志愿者中测定单剂量和多剂量的药物动力学；2)将在多次服用Efavirenz之前和之后评估选定的Cyps的活性。总之，这些研究将为改进治疗奠定基础，通过优化有益效果和避免药物不良反应，增加由CYP2B6代谢的药物清单。