L-Carnitine As A Metabolic Biomarker of Drug Toxicity Risk

左旋肉碱作为药物毒性风险的代谢生物标志物

基本信息

批准号：
10304185
负责人：
GUS R ROSANIA
金额：
$ 52.6万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2019-01-20 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10304185
关键词：
Affect Animals Area Biochemical Pathway Biological Assay Biological Markers Blood Carbon Carnitine Cell physiology Cells Clinical Clinical Trials Critical Illness Decision Making Development Disease Marker Dose Drug Exposure Drug Side Effects Drug toxicity Experimental Models Exposure to Future Glucose tolerance test Goals Health Care Costs Health Status Healthcare Heart Human Impairment Incidence Individual Intestinal Absorption Intestines Intravenous Knowledge Levocarnitine Link Literature Liver Lung Mediating Metabolic Metabolic stress Metabolism Mitochondria Molecular Morbidity - disease rate Mus Oral Organ Organism Outcome Pathway interactions Patient-Focused Outcomes Patients Pattern Pharmaceutical Preparations Pharmacology and Toxicology Pharmacotherapy Phenotype Physiological Predisposition Process Radiolabeled Reaction Regulation Risk Route Scientific Advances and Accomplishments Severity of illness Site Skeletal Muscle Stream Structure System Testing Therapeutic Therapeutic Human Experimentation Toxic effect Toxicology Tracer Variant Withdrawal Work adverse drug reaction base candidate marker clinically relevant design drug candidate drug market experimental study improved in vivo insight metabolic phenotype metabolomics mitochondrial dysfunction monocyte mortality patient population patient stratification peripheral blood precision medicine response risk minimization small molecule uptake validation studies

项目摘要

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.

市场上大多数小分子药物旨在通过口服进入有机体路线。胃肠道滥用后，它们到达血液，药物分子在到达其预期的目标位点之前，在整个身体中循环并分发。在这个过程，细胞内药物在肠，肝，肺，心脏或其他重要器官中的积累可以干扰线粒体功能，使患者患有不良药物反应（ADR）。基于关于对批判性ILL患者的临床试验的结果，L-肉碱已成为候选者，代谢应激生物标志物，可用于固定易于药物诱导的个体线粒体功能中的扰动引起的ADR。人类的初步研究动物支持L-肉碱作为线粒体健康状况的功能性生物标志物患者预后的信息。将小鼠作为实验模型，我们建议建立物理基础，以调节L-肉碱水平的变化血液可以用来识别患有ADR风险增加的个体。并行持续的临床试验，我们建议测试L-肉碱“挑战测试”的有用性，以作为“探测” 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-肉碱作为小鼠的代谢示踪剂，我们将阐明L-肉碱利用率的变化是否与变化有关细胞在特定器官中的线粒体功能。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新建立有关血液中正常水平的L-肉碱水平的水平。彼此之间，我们将详细说明以下特定目的：1）开发一个与临床上的，离体基于细胞的测定系统，以建立联系药物诱导的线粒体扰动，肉碱利用和药物暴露。 2）演示肉碱的血液水平增加与代谢扰动有关对药物治疗的毒理学反应。 3）确定器官特异性变化在体内肉碱挑战之后，不同药物治疗引起的肉碱利用率。这些目标将为L-肉碱的实用性提供直接证据代谢压力，同时将L-肉碱利用率的差异与个人的ADR风险联系起来。结果很重要，因为它们将加强使用L-肉碱挑战的情况在开始之前，单个有机体的代谢适应性在开始之前先发表表型药物疗法。这，我们设想使用L-肉碱挑战来根据患者进行分层代谢应激相关ADR的易感性。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Distinguishing the Concentration- vs. Bioaccumulation-Dependent Immunological and Metabolic Effects of Clofazimine.

DOI：
10.3390/pharmaceutics15092350
发表时间：
2023-09-20
期刊：
Pharmaceutics
影响因子：
5.4
作者：
Willmer AR;Diaz-Espinosa J;Zhou A;Stringer KA;Rosania GR
通讯作者：
Rosania GR

L-Carnitine and Acylcarnitines: Mitochondrial Biomarkers for Precision Medicine.

DOI：
10.3390/metabo11010051
发表时间：
2021-01-14
期刊：
Metabolites
影响因子：
4.1
作者：
McCann MR;George De la Rosa MV;Rosania GR;Stringer KA
通讯作者：
Stringer KA

Quantitative Analysis of the Phase Transition Mechanism Underpinning the Systemic Self-Assembly of a Mechanopharmaceutical Device.

DOI：
10.3390/pharmaceutics14010015
发表时间：
2021-12-22
期刊：
Pharmaceutics
影响因子：
5.4
作者：
Dunne S;Willmer AR;Swanson R;Almeida D;Ammerman NC;Stringer KA;Capparelli EV;Rosania GR
通讯作者：
Rosania GR

Database screening as a strategy to identify endogenous candidate metabolites to probe and assess mitochondrial drug toxicity.

DOI：
10.1038/s41598-023-49443-0
发表时间：
2023-12-12
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
de la Rosa, Mery Vet George;Patel, Dipali;Mccann, Marc R.;Stringer, Kathleen A.;Rosania, Gus R.
通讯作者：
Rosania, Gus R.

Clofazimine-Mediated, Age-Related Changes in Skeletal Muscle Mitochondrial Metabolites.