Genotype-Dependent Drug Interactions

该项目的长期目标是了解人类基因变异如何改变药物。 互动。我们在这里重点研究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的程度的信息 基因会影响这些药物的相互作用。CYP2C9的基因分型尤为重要，因为 酶控制着药物中效力更强的S对映体的代谢失活。因此， 目前的提案解决了核心问题：CYP2C9基因如何修饰华法林药物 有新陈代谢基础的相互作用？这将以下列具体目标实现； 目的1测定健康人华法林-氟康唑抑制药相互作用的大小 志愿者通过检测华法林对映体AUC，Clear， 部分代谢物清除和凝血酶原时间。 目的2测定同一基因型华法林-利福平诱导药物相互作用的大小 目标1中研究的受试者群体。 目的3利用细胞色素P450缺失系统确定替代的P450在S-华法林清除中的作用 具有遗传缺陷的CYP2C9活性的受试者，并开发体外系统来概括 目标1和目标2中描述的体内代谢相互作用。 目的4合成胺碘酮的已知和可疑抑制性代谢物，并测定其结构。 体外对已知有助于华法林清除的P450酶的抑制效力。 目的5确定在华法林患者中，CYP2C9、CYP2C8和稳态基因的作用 血浆胺碘酮及其抑制代谢物水平对华法林剂量调整变异性的影响 接受联合治疗的患者。 目标1和目标2解决了功能缺陷的CYP2C9等位基因可减弱华法氟康唑的假说 抑制相互作用，加剧华法林-利福平诱导相互作用。目标3 提出了一种假设，即CYP2C9缺乏的受试者因代谢相互作用而风险增加 涉及细胞色素P3A4。目标4和目标5针对的假设是华法林-胺碘酮的量值 药物相互作用可以使用有关CYP2C9、CYP2C8和 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 通过提供一个机械框架进行P450抑制剂和诱导剂的治疗，包括 药物基因组学方面的考虑，这将改善在多学科治疗期间对剂量调整的指导 广泛使用的口服抗凝剂。

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.