Metabolite-Dependent Drug Interactions

代谢依赖性药物相互作用

• 批准号: 8380465
• 负责人: KENT L KUNZE
• 金额: $ 33.07万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8380465
• 关键词: Amines; Behavior; Binding; Biological Models; CYP2C19 gene; CYP2D6 gene; CYP3A4 gene; Clinical Research; Complex; Coupled; Cytochrome P450; Data; Diltiazem; Dose; Drug Interactions; Drug Kinetics; Enzyme Inhibition; Enzymes; Evaluation; Event; Failure; Fluoxetine; Goals; Heme Iron; Hepatocyte; Hospitalization; Human; Hydroxylamine; In Vitro; Investigation; Isomerism; Itraconazole; Kinetics; Life; Link; Liver Microsomes; Metabolic Pathway; Metabolism; Methods; Microsomes; Modeling; One-Step dentin bonding system; Parents; Pathway interactions; Pharmaceutical Preparations; Plague; Play; Process; Rationalization; Reaction; Recombinants; Relative (related person); Research; Resolution; Role; Secondary to; Solutions; Source; Stereoisomer; System; Testing; Therapeutic; Therapeutic Agents; Time; Work; base; clinically significant; drug development; drug discovery; drug metabolism; enzyme activity; in vitro Model; in vitro testing; in vivo; inhibitor/antagonist; interest; prospective; research study; tertiary amine; tool

The long-term goal of this project is to better understand drug-drug interactions that arise primarily from the inhibitory effects of drug metabolites, rather than from the effects of the drugs themselves. It is well established that metabolites of drugs can be toxic, pharmacologically active, a cause of clinically significant drug-drug interactions and/or the source of non-linear drug pharmacokinetics. Thus, metabolites often play an important role in therapeutics. Metabolite-based drug interactions that arise from the inhibitory effects of drug metabolites, rather than the parent drugs, on P450 enzyme activity are poorly understood and difficult to predict. Rationalization of these types of interaction requires simultaneous resolution of two of the major scaling issues that plague drug metabolism research - (1) the application of in vitro data for a drug in order to predict in vivo metabolite pharmacokinetics and (2) prediction of the magnitude of a drug-drug interaction caused by a drug (in this case a metabolite) in vivo. The goal of this application is to establish theoreticallybased and experimentally verified means to understand, detect and more reliably predict metabolicallybased drug interactions. Aim 1 completes our in vivo and in vitro work on the stereoselective metabolism of itraconazole (a potent inhibitor of drug metabolism in vivo) and the effects of the long lived, tight binding metabolites on enzyme activity and dose dependent pharmacokinetics of the parent drug. Aim 2 focuses on a rationalization of the magnitude of drug-drug interactions that occur as the result of long term dosing of fluoxetine with drugs that are cleared by CYP2D6, CYP2C19 and CYP3A4 and the role of fluoxetine metabolites in these interactions. Experimental approaches use single recombinant enzymes, hepatocytes and in vivo interaction studies to test our predictions. Aim 3 extends our work on the complexities of the irreversible inhibition of CYP3A4 by diltiazem and it's metabolites in single enzyme systems, microsomes and hepatocytes. The major objective here is to establish and rationalize new methods to meaningfully quantify in vitro behavior when the inhibition is almost entirely driven by the concentrations of diltiazem's metabolites. .Successful completion of these aims will provide powerful new tools to use in the prospective evaluation of metabolite-based drug interactions.

该项目的长期目标是更好地了解主要来自于 药物代谢产物的抑制作用，而不是来自药物本身的作用。很好 确定药物的代谢产物可能是有毒的，药理学活性的，这是临床上显着的原因 药物相互作用和/或非线性药物药代动力学的来源。因此，代谢物经常发挥 在治疗学中的重要作用。基于代谢物的药物相互作用是由 在P450酶活性上的药物代谢产物而不是母体药物的理解较低且困难 预测。这些类型的互动的合理化需要同时解决两个主要的分辨率 缩放困扰药物代谢研究的缩放问题 - （1）将体外数据应用于药物的顺序 预测体内代谢产物药代动力学和（2）预测药物相互作用的大小 由药物（在这种情况下是代谢产物）在体内引起的。该应用程序的目的是建立理论上基于 并经过实验验证的方法来理解，检测并更可靠地预测代谢 药物相互作用。 AIM 1完成了我们的体内和体外工作的立体选择性代谢 Itraconazole（体内药物代谢的有效抑制剂）和长期生存的紧密结合的影响 母体的酶活性和剂量依赖性药代动力学的代谢产物。 AIM 2专注于 由于长期给药的导致药物相互作用的大小的合理化 氟西汀用CYP2D6，CYP2C19和CYP3A4清除的药物以及氟西汀的作用 这些相互作用中的代谢产物。实验方法使用单个重组酶，肝细胞 和体内相互作用研究以测试我们的预测。 AIM 3扩展了我们在复杂性上的工作 diltiazem对CYP3A4的不可逆转抑制作用及其在单个酶系统中的代谢物，微粒体 和肝细胞。这里的主要目的是建立并合理化新方法以有意义 当抑制几乎完全由diltiazem的浓度驱动时，可以量化体外行为 代谢物。这些目标的成功完成将提供有力的新工具，可以在预期中使用 评估基于代谢物的药物相互作用。