Related Experiment Video
Updated: May 7, 2026
Mass Spectrometry and Luminogenic-based Approaches to Characterize Phase I Metabolic Competency of In Vitro Cell Cultures
Published on: March 28, 2017
Elucidation of lorlatinib toxicity mechanisms through GC-MS-based metabolomics
Di Niu1, Shiyuan Zhao2, Shanshan Kong3
1Department of Neurosurgery, Jining No.1 People's Hospital, Shandong First Medical University, Jining 272000, China.
Abstract:
Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor that demonstrates superior efficacy in the treatment of non-small cell lung cancer (NSCLC). However, its toxicological profile remains insufficiently understood. In this study, we employed an untargeted metabolomics approach. Differential metabolites were identified in the hippocampus, cerebral cortex, lungs, and serum between the control and lorlatinib-treated groups of mice. Subsequently, KEGG pathway enrichment analysis was performed on these differential metabolites. The findings suggest that lorlatinib may exert toxicity by disrupting lipid metabolism, linoleic acid metabolism, niacin and nicotinamide metabolism, as well as the synthesis and metabolic pathways of multiple amino acids. This study clarifies the impact of lorlatinib exposure on metabolic profiles across various mouse tissues, identifies metabolism-related pathways linked to lorlatinib toxicity, and provides new insights into its toxicological mechanisms.
Insights
Lorlatinib, an ALK inhibitor for non-small cell lung cancer, may cause toxicity by disrupting lipid, linoleic acid, niacin, and amino acid metabolism. This study reveals lorlatinib
Area of Science:
- Pharmacology
- Metabolomics
- Toxicology
Background:
- Lorlatinib is a third-generation ALK inhibitor effective against non-small cell lung cancer (NSCLC).
- The toxicological profile of lorlatinib is not fully understood.
- Understanding lorlatinib's toxicity is crucial for patient safety.
Purpose of the Study:
- To investigate the toxicological mechanisms of lorlatinib using metabolomics.
- To identify specific metabolic pathways affected by lorlatinib exposure in mice.
Main Methods:
- Untargeted metabolomics was performed on mouse hippocampus, cerebral cortex, lungs, and serum.
- Differential metabolites were identified between control and lorlatinib-treated groups.
- KEGG pathway enrichment analysis was conducted on identified metabolites.
Main Results:
- Lorlatinib exposure altered metabolite profiles in multiple tissues and serum.
- Key disrupted pathways include lipid metabolism, linoleic acid metabolism, niacin and nicotinamide metabolism, and amino acid metabolism.
- Significant changes were observed in the brain, lungs, and systemic circulation.
Conclusions:
- Lorlatinib toxicity may stem from disruptions in lipid, niacin, and amino acid metabolism.
- Metabolomic analysis provides insights into lorlatinib's tissue-specific effects.
- This study elucidates potential mechanisms underlying lorlatinib-induced toxicity.
More Related Videos
06:14Optimized LC-MS/MS Method for the High-throughput Analysis of Clinical Samples of Ivacaftor, Its Major Metabolites, and Lumacaftor in Biological Fluids of Cystic Fibrosis Patients
Published on: October 15, 2017
11:06Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
