Metabolic Phenotyping and Pharmocokinetics Core

代谢表型和药代动力学核心

• 批准号: 9981039
• 负责人: ROBERT E GERSZTEN
• 金额: $ 38.47万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981039
• 关键词: Agonist; Amines; Amino Acids; Animal Model; Automobile Driving; Bile Acids; Biological Assay; Blood; Carbon; Chemicals; Citric Acid Cycle; Creatinine; Cyanides; Data; Development; Drug Kinetics; Enzymes; Family suidae; Formulation; Generations; Goals; Homeostasis; Indoles; Institutes; Intervention Studies; Intoxication; Investigational Therapies; Lactate Dehydrogenase; Lead; Lipids; Measurement; Measures; Mediating; Metabolic; Methods; Modeling; Modification; Monitor; Oryctolagus cuniculus; Oxidation-Reduction; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Platinum; Purines; Pyrimidines; Rattus; Role; Safety; Scanning; Science; Secondary to; Serum; Sugar Phosphates; Techniques; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; Uric Acid; Urine; base; complex IV; diagnostic biomarker; dosage; drug metabolism; efficacy study; efficacy testing; experimental study; glyoxylate; in vivo; instrument; lead candidate; liquid chromatography mass spectrometry; metabolic abnormality assessment; metabolic phenotype; metabolic profile; metabolomics; novel; novel diagnostics; organic acid; response; synergism; therapeutic development

Metabolic Phenotyping and Pharmacokinetics (MPPK) Core SUMMARY The MPPK Core will leverage a robust LC-MS/MS-based platform to: 1) Perform detailed pharmacokinetic (PK) studies of countermeasures; 2) Identify metabolic surrogates that track with the efficacy of countermeasures, as well as unanticipated off-target effects; 3) Identify very early markers of cyanide toxicity or persistent changes after prior transient exposure so that countermeasures can be instituted at the earliest possible juncture; 4) Identify the broad spectrum of metabolic derangements secondary to cyanide toxicity thus highlighting enzymes or metabolites for therapeutic intervention. For Project 1 (Hexachloroplatinate [HCP]), the Core will allow us to assess initial drug metabolism and pharmacokinetic (DMPK) attributes of platinum and related compounds under study. Further, because the platform is sensitive to pharmacological perturbations, studies of countermeasures in mammalian species may help us judge their relative safety and potential off-target effects. For Project 2 (Glyoxylate), the core will perform detailed PK studies of glyoxylate formulations and second generation glyoxylate derivatives. Additionally, metabolic tracing experiments focused on flux through lactate dehydrogenase (LDH) will enable the identification of complementary targets for countermeasure development. For Project 3 (Metabolic modulators), the core provides a particularly central support role given its focus on TCA cycle intermediates. Each of the aims proposes mechanistic metabolism studies that will heavily rely on the Core. These include the metabolic response to TCA cycle activators, one-carbon pathway agonists and other experimental therapeutics. The platform will also provide a more detailed understanding of the metabolic response to cyanide itself and how inhibition of Complex IV mediates that response. The MPPK Core will also provide synergy for other facets of our proposal, including iterative pharmacokinetic studies in conjunction with the Pharmaceutical Sciences Core. Thus, while the main goal of the platform will be to progress compounds along the therapeutic development pathway, our studies to date also highlight how the platform can provide additional scientific value. Embedded within our studies of interventions are clear opportunities to identify new diagnostic markers both of cyanide intoxication itself as well as effective rescue. A more complete understanding of the broad spectrum of metabolic derangements secondary to cyanide toxicity may highlight additional enzymes or specific metabolites that may be used as therapeutic interventions.

代谢表型和药代动力学（MPPK）核心 概括 MPPK核心将利用强大的LC-MS/MS平台到：1）执行详细的药代动力学 （PK）对策的研究； 2）确定具有效力的代谢替代物 对策以及意外的脱靶效应； 3）确定氰化物毒性的早期标记 或先前的瞬态暴露后持续变化，以便最早建立对策 可能的关头； 4）确定继发于氰化物毒性的代谢危险的广泛频谱 突出酶或代谢物进行治疗干预。 对于项目1（Hexachachloroplatinate [HCP]），核心将使我们能够评估初始药物代谢和 铂和相关化合物的药代动力学（DMPK）属性。此外，因为 平台对药理扰动敏感，对哺乳动物物种的对策的研究可能 帮助我们判断他们的相对安全性和潜在的脱靶效应。 对于项目2（乙二醇），核心将对乙氧基制剂进行详细的PK研究和第二个研究 产生乙二醇衍生物。此外，代谢追踪实验集中于乳酸通量 脱氢酶（LDH）将使能够鉴定互补靶标的来对策开发。 对于项目3（代谢调节剂），核心提供了特别的核心支持角色，鉴于其专注于 TCA循环中间体。每个目标都提出了机械代谢研究，这些研究将在很大程度上依赖 核心。这些包括对TCA循环激活剂，单碳途径激动剂和 其他实验治疗学。该平台还将提供对代谢的更详细的理解 对氰化物本身的反应以及对复合物IV的抑制如何介导该反应。 MPPK核心还将为我们提案的其他方面提供协同作用，包括迭代药代动力学 与药学科学核心结合的研究。因此，尽管平台的主要目标将 要沿着治疗发展途径进行进步，我们迄今为止的研究也强调了如何 该平台可以提供更多的科学价值。嵌入在我们的干预研究中很明确 鉴定氰化物中毒本身的新诊断标记的机会以及有效的救援。 对氰化物继发的代谢危险的广泛范围更完整地理解 毒性可能突出可能用作治疗干预措施的其他酶或特定的代谢产物。