L-Carnitine As A Metabolic Biomarker of Drug Toxicity Risk

市场上的大多数小分子药物被设计为通过口服药物进入生物体。 路线一旦它们在胃肠道吸收后到达血液， 在到达其预定的目标部位之前，在整个身体中循环和分布。在这 在这一过程中，肠、肝、肺、心脏或其他重要器官中的细胞内药物积累可 干扰线粒体功能，使患者易发生药物不良反应（ADR）。基于 根据在危重患者中进行的临床试验的结果，L-肉毒碱已成为候选药物， 代谢应激生物标志物，可用于确定易受药物诱导的个体 线粒体功能紊乱引起的ADR。人类的初步研究， 动物支持L-肉碱作为线粒体健康状态的功能生物标志物， 患者结局的信息。以小鼠作为实验模型，我们建议 建立的生理基础，其中在调节L-肉碱水平的变化， 血液可用于识别ADR风险增加的个体。正在进行的临床试验 试验，我们建议测试的有用性，左旋肉碱“挑战试验”，作为一个“探针”， 询问生物体的代谢适应性及其与药物相关的联系 毒理学表现通过使用放射性标记的L-肉毒碱作为小鼠的代谢示踪剂， 将阐明L-肉碱利用率的变化是否与 特定器官中细胞的线粒体功能。我们还将评估药物对器官的影响- 左旋肉碱的摄取和代谢的特定模式与重建 血液中左旋肉碱的正常水平因此，我们将详细阐述以下具体内容： 目的：1）开发一种临床相关的、基于离体细胞的测定系统，以建立 药物诱导的线粒体扰动、肉毒碱利用和药物暴露。2)证明 血液中肉毒碱水平的增加与代谢紊乱有关， 对药物治疗的毒理学反应。3)确定器官特异性变异 在体内肉毒碱攻击后，不同药物治疗诱导的肉毒碱利用率。 这些目标将提供直接证据的有用性左旋肉碱作为一个指标， 代谢压力，而联系在L-肉毒碱利用的差异，以个人的风险ADR。 结果是显著的，因为它们将加强使用L-肉毒碱挑战的情况， 在开始之前，预先表型个体生物体的代谢适应性， 药物治疗因此，我们设想使用L-肉毒碱挑战，根据患者的 易患代谢应激相关ADR。

Most small molecule drugs on the market are designed to enter the organism via the oral route. Once they reach the blood stream following gastrointestinal absorption, drug molecules circulate and distribute throughout the body before reaching their intended target site(s). In this process, intracellular drug accumulation in the intestine, liver, lung, heart or other vital organs can perturb mitochondrial function, predisposing patients to adverse drug reactions (ADRs). Based on results of a clinical trial in critically-ill patients, L-carnitine has emerged as a candidate, metabolic stress biomarker that can be used to pin-point individuals predisposed to drug-induced ADRs caused by perturbations in mitochondrial function. Preliminary studies in humans and animals support L-carnitine as a functional biomarker of mitochondrial health status that can be informative of patient outcomes. Turning to mice as an experimental model, we propose to establish the physiological basis for which variations in the regulation of L-carnitine levels in the blood can serve to identify individuals at increased risk of ADRs. Paralleling an ongoing clinical trial, we propose to test the usefulness of an L-carnitine “challenge test” to serve as a “probe” to interrogate the metabolic adaptiveness of the organism and its connection to drug-related toxicological manifestations. By using radiolabeled L-carnitine as a metabolic tracer in mice, we will elucidate whether variations in L-carnitine utilization is associated with variations in mitochondrial function of cells in specific organs. We will also assess how drug effects on organ- specific patterns of L-carnitine uptake and metabolism are associated with the re-establishment of normal levels of L-carnitine in the blood. Accordingly, we will elaborate the following specific aims: 1) Develop a clinically-relevant, ex vivo cell-based assay system to establish links between drug-induced mitochondrial perturbations, carnitine utilization and drug exposure. 2) Demonstrate that increased blood levels of carnitine are associated with metabolic perturbations and toxicological reactions in response to drug treatment. 3) Determine the organ-specific variations in carnitine utilization induced by different drug treatments following an in vivo carnitine challenge. These aims will provide direct evidence for the usefulness of L-carnitine as an indicator of metabolic stress, while linking differences in L-carnitine utilization to an individual's risk of ADRs. The results are significant, as they will strengthen the case for using an L-carnitine challenge to pre-emptively phenotype an individual organism's metabolic adaptiveness prior to initiation of drug therapy. Thus, we envision using an L-carnitine challenge to stratify patients based on their predisposition to metabolic stress-related ADRs.