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L-Carnitine As A Metabolic Biomarker of Drug Toxicity Risk

Award Number: R01GM127787
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/20/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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L-Carnitine As A Metabolic Biomarker of Drug Toxicity Risk - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	4	5/30/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	4	1/25/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $526,003 )
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	001	4	7/21/2022	NON-COMPETING CONTINUATION	$52,602
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	4	11/11/2021	NON-COMPETING CONTINUATION	$473,401
2022	2022	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	002	4	7/27/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $526,003

Issue Date FY: 2021 ( Subtotal = $502,834 )
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	3	11/17/2020	NON-COMPETING CONTINUATION	$452,549
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	001	3	2/16/2021	NON-COMPETING CONTINUATION	$50,285
														Subtotal = $502,834

Issue Date FY: 2020 ( Subtotal = $492,798 )
2020	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	001	2	3/5/2020	NON-COMPETING CONTINUATION	$49,280
2020	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	2	11/26/2019	NON-COMPETING CONTINUATION	$443,518
														Subtotal = $492,798

Issue Date FY: 2019 ( Subtotal = $511,928 )
2019	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	1	1/15/2019	NEW	$511,928
2019	2019	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	001	1	9/11/2019	NEW	$0
														Subtotal = $511,928

Grand Total All Awards = $2,033,563

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L-Carnitine As A Metabolic Biomarker of Drug Toxicity Risk

Award Number: R01GM127787

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/20/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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