Genotype-Dependent Drug Interactions

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 交互.我们在这里集中在代谢相互作用涉及广泛使用的口服抗凝药物， 华法林几十年来，Warfare为研究药物-药物作用机制提供了一个模型系统。 相互作用，但没有信息是在多大程度上，共同多态性在华法林反应 基因影响这些药物相互作用。CYP2C9基因型特别重要，因为这 酶控制药物的更有效的S-对映体的代谢失活。因此 目前的建议解决了中心问题：CYP2C9基因型如何改变华法林药物 有代谢基础的相互作用这将通过以下具体目标来实现： 目的1测定华法林-氟康唑在健康人体内的相互作用强度 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。 目的2确定华法林-利福平诱导药物相互作用的大小在相同的基因型 目标1中研究的受试者人群。 目的3利用CYP2C9无效系统，确定替代P450在S-华法林清除中的作用， 受试者与基因受损的CYP2C9活性，并开发体外系统，以概括在 在目标1和2中表征的体内代谢相互作用。 目的4合成胺碘酮的已知和疑似抑制性代谢产物，并测定其结构 对已知有助于华法林清除的P450酶的体外抑制效力。 目的5明确华法林患者CYP2C9、CYP2C8基因型与稳态代谢的关系 胺碘酮及其抑制性代谢产物的血浆水平与华法林剂量调整的变异性之间的关系， 接受联合治疗的患者。 目的1和2阐明了功能缺陷的CYP2C9等位基因可减弱戊唑醇的假设 抑制性相互作用并加剧华法林-利福平诱导性相互作用。目标3 阐述了CYP2C9缺陷受试者代谢相互作用风险增加的假设 涉及CYP3A4。目的4和5阐述了华法林-胺碘酮的剂量大小 药物相互作用可以使用关于CYP2C9、CYP2C8和CYP2C9基因型状态的信息来预测。 胺碘酮的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 通过提供一种机制框架，结合 药物基因组学考虑，这将改善在多药治疗期间的剂量调整指导， 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.