Metabolic Phenotyping and Pharmocokinetics Core

代谢表型和药代动力学(MPPK)核心 摘要 MPPK Core将利用基于LC-MS/MS的强大平台：1)执行详细的药代动力学 (Pk)对策研究；2)确定跟踪药物疗效的代谢物 对策以及意想不到的偏离目标的影响；3)确定氰化物毒性的非常早期的标志 或在先前的短暂接触后的持续变化，以便尽早采取对策 可能的结合点；4)确定氰化物中毒继发的广泛代谢紊乱，从而 强调用于治疗干预的酶或代谢物。 对于项目1(六氯铂酸盐[HCP])，核心将使我们能够评估最初的药物代谢和 正在研究的铂及其相关化合物的药代动力学(DMPK)属性。此外，因为 Platform对药物扰动很敏感，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)，核心将对乙醛配方进行详细的PK研究，第二 生成乙醛酸衍生物。此外，代谢示踪实验的重点是通过乳酸盐的通量 脱氢酶(LDH)将有助于确定制定对策的补充目标。 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 三氯乙烷循环中间体。每个目标都提出了机械性新陈代谢研究，这些研究将严重依赖于 核心。这些包括对TCA循环激活剂、单碳途径激动剂和 其他实验性疗法。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，以及抑制复合体IV如何调节这种反应。 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 与药学核心联合进行的研究。因此，虽然平台的主要目标将是 为了使化合物在治疗发展道路上取得进展，我们迄今的研究也强调了如何 该平台可以提供额外的科学价值。在我们的干预研究中嵌入的是清楚的 找出氰化物中毒本身和有效抢救的新诊断标志物的机会。 更全面地了解继发于氰化物的广泛代谢紊乱 毒性可能突出可用作治疗干预的其他酶或特定代谢物。

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.