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

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $502,834

## Abstract

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.

## Key facts

- **NIH application ID:** 10063004
- **Project number:** 5R01GM127787-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** GUS R ROSANIA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $502,834
- **Award type:** 5
- **Project period:** 2019-01-20 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10063004

## Citation

> US National Institutes of Health, RePORTER application 10063004, L-Carnitine As A Metabolic Biomarker of Drug Toxicity Risk (5R01GM127787-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10063004. Licensed CC0.

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