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.

Public Health Relevance

Scientific advances to identify individuals predisposed to serious drug side effects and minimize the risk of adverse drug reactions (ADRs) will transform health care by: i) reducing the incidence of drug-related morbidity and mortality; ii) reducing withdrawal of otherwise effective drugs from the market; and, iii) facilitating development of more potent, safer drugs. Using functional biomarkers of ADR risk to stratify patients and identify individuals at risk of ADRs will help improve therapeutic decision making, which will benefit patients across all therapeutic areas.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM127787-01A1
Application #
9661288
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
2019-01-20
Project End
2022-11-30
Budget Start
2019-01-20
Budget End
2019-11-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109