Pharmacogenetics and Drug Interactions

药物遗传学和药物相互作用

• 批准号: 7267686
• 负责人: TIMOTHY S. TRACY
• 金额: $ 22.75万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-04-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7267686
• 关键词: Active Sites; Address; Affect; Alleles; Amino Acid Substitution; Amino Acids; Amitriptyline; Binding; CYP2C9 gene; CYP2D6 gene; Chemical Structure; Clinical Research; Codeine; Computer Simulation; Cytochrome P450; Data; Dose; Drug Delivery Systems; Drug Interactions; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzyme Kinetics; Enzymes; Exhibits; Fluconazole; Flurbiprofen; Foundations; Genetic Polymorphism; Genotype; Goals; Heme; Heme Iron; Human; In Vitro; Individual; Kinetics; Knowledge; Liver Microsomes; Measures; Mediating; Metabolism; Modeling; Patients; Pharmaceutical Preparations; Pharmacogenetics; Phenytoin; Predisposition; Proteins; Relative (related person); Research; Role; Structure; Testing; Variant; Warfarin; base; clinically relevant; dosage; drug clearance; genetic variant; improved; in vivo; inhibitor/antagonist; predictive modeling; programs; research study; size

DESCRIPTION (provided by applicant): Polymorphisms in cytochrome P450 enzymes, such as CYP2C9 and CYP2D6, may not only affect drug clearance but may affect patient's susceptibility to drug inhibition interactions. The long term goal of this research is to understand the role of amino acid substitution due to polymorphisms in P450 enzymes in the relative susceptibility to drug-drug interactions. The metabolism of several clinically relevant drugs is greatly diminished in subjects with CYP2C9 and CYP2D6 polymorphisms, necessitating dosage adjustments. Since amino acid changes resulting from polymorphisms can affect substrate binding and turnover, inhibitor binding and effect can also be altered. Because substrates and inhibitors may bind within a P450 active site in different orientations, the degree and direction of change in inhibition is likely to be both inhibitor and genotype dependent. The proposed experiments will study common variants of CYP2C9 and CYP2D6 with known inhibitors of these enzymes and assess the degree and type of inhibition observed. T1 NMR experiments will be conducted to determine the distances and relative orientation of substrate and inhibitor from heme iron for incorporation with kinetic data into computer models predictive of drug inhibition potential based on the polymorphic form of the enzyme. Finally, differences in inhibition due to genotype will be tested in vivo with a human clinical study of drug inhibition in patients of two different CYP2C9 genotypes. Taken together, these studies will permit a better understanding of drug inhibition potential in different P450 genotypes and serve as a foundation for increasing our understanding of interindividual differences in susceptibility to drug interactions

描述（由申请人提供）：细胞色素P450酶（例如CYP2C9和CYP2D6）中的多态性不仅可能影响药物清除率，而且可能影响患者对药物抑制相互作用的敏感性。这项研究的长期目标是了解由于P450酶在药物相互作用的相对敏感性中，由于多态性在P450酶中的作用。在CYP2C9和CYP2D6多态性的受试者中，几种临床相关药物的代谢大大降低，需要进行剂量调整。由于由多态性引起的氨基酸变化会影响底物的结合和周转，因此抑制剂的结合和效果也可以改变。由于底物和抑制剂可以在不同方向的P450活性位点内结合，因此抑制作用的程度和方向可能既可能是抑制剂和基因型依赖性的。提出的实验将研究CYP2C9和CYP2D6的常见变体，并具有这些酶的已知抑制剂，并评估观察到的抑制程度和类型。将进行T1 NMR实验，以确定血红素铁中底物和抑制剂的距离和相对取向，以将动力学数据与计算机模型合并到计算机模型中，以预测基于酶的多态性形式的药物抑制潜力。最后，通过对两种不同CYP2C9基因型的患者的药物抑制作用，将在体内对基因型抑制作用的差异进行测试。综上所述，这些研究将使对不同P450基因型的药物抑制潜力有更好的了解，并为我们对药物相互作用易感性的个人间差异的理解提供了基础