Genotype-Dependent Drug Interactions

基因型依赖性药物相互作用

• 批准号: 7559316
• 负责人: Allan Edward Rettie
• 金额: $ 52.17万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7559316
• 关键词: Address; Affect; Alleles; Amiodarone; Anticoagulants; Attenuated; Biological Models; CYP2C9 gene; CYP3A4 gene; Caring; Clinical; 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; 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 互动。我们在这里关注涉及广泛使用的口服抗凝药物的代谢相互作用， 华法林。几十年来，华法林为研究药物-药物机制提供了一个模型系统 相互作用，但没有关于华法林反应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 基因型尤其重要，因为 酶控制药物更有效的 S-对映体的代谢失活。因此， 当前的提案解决了核心问题； CYP2C9基因型如何改变华法林药物 具有代谢基础的相互作用？这将通过以下具体目标来实现； 目标 1 确定健康人群中华法林-氟康唑抑制药物相互作用的程度 通过测量华法林对映体 AUC、清除率，对志愿者进行 CYP2C9*1/ *1、*1/*3 或 *3/*3 基因分型， 部分代谢物清除率和凝血酶原时间。 目标 2 确定同一基因型中华法林-利福平诱导药物相互作用的程度 目标 1 中研究的受试者群体。 目标 3 利用 CYP2C9 无效系统确定替代 P450 在 S-华法林清除中的作用 CYP2C9 活性基因受损的受试者，并开发体外系统以重现体内 目标 1 和 2 中表征的体内代谢相互作用。 目标 4 合成已知和可疑的胺碘酮抑制代谢物，并测定其 体外对已知有助于华法林清除的 P450 酶的抑制效力。 目标 5 定义华法林患者中 CYP2C9 基因型、CYP2C8 基因型和稳态的贡献 胺碘酮及其抑制性代谢物的血浆水平，与华法林剂量调整的变异性 接受联合治疗的患者。 目标 1 和 2 提出了功能缺陷 CYP2C9 等位基因会减弱华法林氟康唑的假设 抑制相互作用并加剧华法林-利福平诱导相互作用。目标 3 解决了 CYP2C9 缺陷受试者代谢相互作用风险增加的假设 涉及 CYP3A4。目标 4 和 5 提出了以下假设：华法林-胺碘酮的作用强度 可以使用有关 CYP2C9、CYP2C8 和 CYP2C8 基因型状态的信息来预测药物相互作用。 胺碘酮循环抑制代谢物的血浆浓度。 这些研究的成功完成有望改善华法林患者的临床护理 通过提供机制框架接受 P450 抑制剂和诱导剂治疗，结合 药物基因组学考虑，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。