L-Carnitine As A Metabolic Biomarker of Drug Toxicity Risk

市场上的大多数小分子药物都是通过口服进入机体的。 路线。一旦它们在胃肠道吸收后到达血流，药物分子 在到达预定的目标部位之前，在全身循环和分配(S)。在这 过程中，细胞内药物在肠、肝、肺、心脏或其他重要器官中的积聚可以 扰乱线粒体功能，使患者容易出现药物不良反应(ADRs)。基座 根据危重病患者的临床试验结果，L-卡尼汀已成为候选药物， 代谢应激生物标记物，可用于锁定药物诱发的易感个体 线粒体功能紊乱引起的不良反应。对人类和人类的初步研究 动物支持L肉碱作为线粒体健康状态的功能性生物标志物 患者结果的信息性。以小鼠为实验模型，我们建议 建立L肉碱水平调节变化的生理基础 血液可以用来识别ADR风险增加的个人。与正在进行的临床 试验中，我们建议测试L肉碱“挑战试验”的有用性，以此作为“探查” 询问机体的代谢适应性及其与药物相关的联系 毒物学表现。通过使用放射性标记的L肉碱作为小鼠的代谢示踪剂，我们 将阐明L肉碱利用的变化是否与 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- L肉碱摄取和代谢的特定模式与重建有关 L血液中肉碱的正常水平。据此，我们将详细阐述以下具体内容 目标：1)开发一种临床相关的、基于体外细胞的检测系统，以建立 药物引起的线粒体紊乱、肉碱利用和药物暴露。2)演示 血液中肉碱水平的升高与新陈代谢紊乱有关 药物治疗反应的毒理学反应。3)确定特定器官的变异 在体内肉碱挑战后不同药物治疗诱导的肉碱利用。 这些目的将为L-卡尼汀作为一种指标的有效性提供直接证据 代谢压力，同时将L-卡尼汀的使用差异与个人的不良反应风险联系起来。 结果是意义重大的，因为它们将加强使用L-肉碱挑战 先发制人的表型个体有机体的代谢适应性在启动之前 药物治疗。因此，我们设想使用L肉碱挑战来根据患者的情况对患者进行分层 易患代谢应激相关的不良反应。

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.