Genotype-Dependent Drug Interactions

基因型依赖性药物相互作用

• 批准号: 8334083
• 负责人: Allan Edward Rettie
• 金额: $ 36.13万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334083
• 关键词: Address; Affect; Alleles; Amiodarone; Anticoagulants; Attenuated; Biological Models; CYP2C9 gene; CYP3A4 gene; Combined Modality Therapy; Complex; Cytochrome P450; Dose; Drug Interactions; Enzymes; Fluconazole; Genes; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Homozygote; Human; Human Genetics; In Vitro; Linkage Disequilibrium; Measures; Metabolic; Metabolism; Modeling; Monitor; Oral; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenomics; Plasma; Population; Population Study; Prothrombin time assay; Recruitment Activity; Rifampin; Risk; Role; Staging; System; Variant; Warfarin; base; clinical care; drug mechanism; enantiomer; fascinate; healthy volunteer; improved; in vivo; inhibitor/antagonist; insight; response

The long-term goal of this project is to understand how human genetic variation modifies drug-drug interactions. We focus here on metabolic interactions involving the widely used oral anticoagulant drug, warfarin. Warfarin has, for many decades, provided a model system for studying mechanisms of drug-drug interactions, but no information is available as to the extent to which common polymorphisms in warfarinresponse genes affect these drug interactions. CYP2C9 genotype is particularly important because this enzyme governs the metabolic inactivation of the more potent S-enantiomer of the drug. Consequently, the current proposal addresses the central question; How does CYP2C9 genotype modify warfarin drug interactions that have a metabolic basis? This will be accomplished with the following specific aims; Aim 1 Determine the magnitude of the warfarin-fluconazole inhibitory drug interaction in healthy volunteers genotyped for CYP2C9*1/ *1, *1/*3 or *3/*3 by measuring warfarin enantiomer AUC, clearance, partial metabolite clearances, and prothrombin time. Aim 2 Determine the magnitude of the warfarin-rifampin inductive drug interaction in the same genotyped subject population studied in Aim 1. Aim 3 Exploit CYP2C9 null systems to determine the role of alternative P450s in S-warfarin clearance in subjects with genetically compromised CYP2C9 activity, and develop in vitro systems to recapitulate the in vivo metabolic interactions characterized in Aims 1 and 2. Aim 4 Synthesize known and suspected inhibitory metabolites of amiodarone, and determine their inhibitory potency in vitro against P450 enzymes known to contribute to warfarin clearance. Aim 5 Define, in warfarin patients, the contribution of CYP2C9 genotype, CYP2C8 genotype and steadystate plasma levels of amiodarone and its inhibitory metabolites, to variability in warfarin dose adjustment in patients receiving combination therapy. Aims 1 and 2 address the hypothesis that functionally defective CYP2C9 alleles attenuate the warfarinfluconazole inhibitory interaction and exacerbate the warfarin-rifampin inductive interaction. Aim 3 addresses the hypothesis that CYP2C9-deficient subjects are at increased risk from metabolic interactions involving CYP3A4. Aims 4 and 5 address the hypothesis that the magnitude of the warfarin-amiodarone drug interaction can be predicted using information about the genotype status for CYP2C9, CYP2C8, and the plasma concentration of circulating inhibitory metabolites of amiodarone. Successful completion of these studies is expected to improve clinical care of warfarin patients undergoing treatment with P450 inhibitors and inducers by providing a mechanistic framework, incorporating pharmacogenomic considerations, that will improve guidance of dose adjustment during polytherapy with this widely used oral anticoagulant.

该项目的长期目标是了解人类遗传变异如何改变药物药物 互动。我们在这里专注于代谢相互作用，涉及广泛使用的口服抗凝药物， 华法林。华法林（Warfarin 相互作用，但没有有关Warfarinresponse中常见多态性的程度的信息 基因影响这些药物相互作用。 CYP2C9基因型特别重要，因为这 酶控制着药物更有效的S-耐象体的代谢失活。因此， 当前的提议解决了一个核心问题； CYP2C9基因型如何修饰华法林药物 具有代谢基础的互动？这将通过以下特定目标来实现； AIM 1确定健康中华法蛋白 - 氟康唑抑制性药物相互作用的大小 通过测量Warfarin onantiomer auc，清除率 部分代谢物清除和凝血酶原时间。 AIM 2确定在同一基因分型中的华法蛋白 - 里佛蛋白电感药物相互作用的大小 在AIM 1中研究的受试者人群。 AIM 3利用CYP2C9无效系统来确定替代P450在S-Warfarin清除中的作用 具有遗传损害的CYP2C9活性的受试者，并开发体外系统以概括IN 在目标1和2中表征的体内代谢相互作用。 AIM 4合成已知和怀疑的胺碘酮抑制代谢物，并确定其 对P450酶的抑制效力已知有助于华法林清除。 AIM 5在华法林患者中定义了CYP2C9基因型，CYP2C8基因型和Steadystate的贡献 氨二酮及其抑制性代谢产物的血浆水平，以调整华法林剂量的变异性 接受联合疗法的患者。 目标1和2解决了功能有缺陷的CYP2C9等位基因衰减Warfarinfluconazole的假设 抑制性相互作用并加剧华法蛋白 - 瑞佛蛋白电感相互作用。目标3 解决了以下假设：CYP2C9缺陷受试者的代谢相互作用增加了风险 涉及CYP3A4。目的4和5解决了华法林 - 氨二元的大小的假设 可以使用有关CYP2C9，CYP2C8和 胺碘酮循环抑制代谢产物的血浆浓度。 这些研究的成功完成有望改善华法林患者的临床护理 通过提供机械框架，通过P450抑制剂和诱导剂进行治疗 药物基因组学的考虑，这将改善多疗法期间剂量调整的指导 广泛使用的口服抗凝剂。