Metabolic Phenotyping and Pharmocokinetics Core

代谢表型和药代动力学核心

基本信息

批准号：
10241496
负责人：
ROBERT E GERSZTEN
金额：
$ 38.24万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/10241496
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 metabolomics novel novel diagnostics organic acid response synergism therapeutic development

项目摘要

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 核心将利用基于 LC-MS/MS 的强大平台来：1) 执行详细的药代动力学（PK）对策研究； 2) 确定跟踪功效的代谢替代物对策以及意外的脱靶效应； 3) 识别氰化物毒性的早期标志物或在先前短暂暴露后发生持续变化，以便尽早采取应对措施可能的接合点； 4) 识别继发于氰化物毒性的广谱代谢紊乱，从而强调用于治疗干预的酶或代谢物。对于项目 1（六氯铂 [HCP]），核心将使我们能够评估初始药物代谢和正在研究的铂及相关化合物的药代动力学 (DMPK) 属性。此外，由于平台对药理扰动敏感，哺乳动物物种的对策研究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（乙醛酸盐），核心将进行乙醛酸盐制剂和第二次详细的 PK 研究。生成乙醛酸衍生物。此外，代谢追踪实验的重点是乳酸的通量脱氢酶（LDH）将能够确定对策开发的补充目标。对于项目 3（代谢调节剂），核心提供了特别核心的支持作用，因为它的重点是 TCA循环中间体。每个目标都提出了机械代谢研究，这些研究将在很大程度上依赖于核心。这些包括对 TCA 循环激活剂、一碳途径激动剂和其他实验疗法。该平台还将提供对代谢的更详细的了解对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与制药科学核心联合研究。因此，虽然该平台的主要目标是为了沿着治疗开发途径推进化合物，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。我们的干预研究中的内容是明确的有机会识别氰化物中毒本身以及有效救援的新诊断标志物。更全面地了解氰化物继发的广泛代谢紊乱毒性可能会突出可用作治疗干预的其他酶或特定代谢物。