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 总结 MPPK核心将利用强大的基于LC-MS/MS的平台：1）进行详细的药代动力学研究 (PK)对策的研究; 2）确定代谢替代物，跟踪的功效， 对策，以及意外脱靶效应; 3）识别氰化物毒性的早期标志物 或在先前短暂暴露之后的持续变化，以便能够尽早制定对策 可能的结合点; 4）确定继发于氰化物毒性的广泛的代谢紊乱， 突出用于治疗干预的酶或代谢物。 对于项目1（六氯铂酸盐[HCP]），核心将允许我们评估初始药物代谢， 研究中的铂和相关化合物的药代动力学（DMPK）属性。此外，由于 平台对药理学干扰敏感，在哺乳动物物种中研究对策可能 帮助我们判断它们的相对安全性和潜在的脱靶效应。 对于项目2（乙醛酸），核心将进行乙醛酸制剂的详细PK研究， 生成乙醛酸衍生物。此外，代谢示踪实验侧重于通过乳酸的通量 脱氢酶（LDH）的测定将有助于确定制定对策的互补目标。 对于项目3（代谢调节剂），核心提供了一个特别重要的支持作用，因为它的重点是 TCA循环中间体。每个目标都提出了代谢机制研究，这些研究将严重依赖于 核心的这些包括对TCA循环激活剂、一碳途径激动剂和 其他实验性疗法。该平台还将提供对代谢的更详细的了解。 氰化物本身的反应以及复合物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 研究与药学科学核心。因此，虽然该平台的主要目标是 为了使化合物沿着治疗开发途径发展，我们迄今为止的研究还强调了如何 该平台可以提供额外的科学价值。在我们的干预研究中， 有机会确定新的诊断标志物氰化物中毒本身以及有效的救援。 对氰化物继发代谢紊乱的广谱性更全面的了解 毒性可能会突出显示可用作治疗干预的其他酶或特定代谢物。