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A Comprehensive Analysis of Metabolomics and Transcriptomics Reveals Novel Biomarkers and Mechanistic Insights on Lorlatinib Crosses the Blood-Brain Barrier
Of late, lorlatinib has played an increasingly pivotal role in the treatment of brain metastasis from non-small cell lung cancer. However, its pharmacokinetics in the brain and the mechanism of entry are still controversial. The purpose of this study was to explore the mechanisms of brain penetratio...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419651/ https://www.ncbi.nlm.nih.gov/pubmed/34497521 http://dx.doi.org/10.3389/fphar.2021.722627 |
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author | Chen, Wei Li, Chunyu Shi, Yafei Zhang, Yujun Jin, Dujia Zhang, Mingyu Bo, Mingming Li, Guohui |
author_facet | Chen, Wei Li, Chunyu Shi, Yafei Zhang, Yujun Jin, Dujia Zhang, Mingyu Bo, Mingming Li, Guohui |
author_sort | Chen, Wei |
collection | PubMed |
description | Of late, lorlatinib has played an increasingly pivotal role in the treatment of brain metastasis from non-small cell lung cancer. However, its pharmacokinetics in the brain and the mechanism of entry are still controversial. The purpose of this study was to explore the mechanisms of brain penetration by lorlatinib and identify potential biomarkers for the prediction of lorlatinib concentration in the brain. Detection of lorlatinib in lorlatinib-administered mice and control mice was performed using liquid chromatography and mass spectrometry. Metabolomics and transcriptomics were combined to investigate the pathway and relationships between metabolites and genes. Multilayer perceptron was applied to construct an artificial neural network model for prediction of the distribution of lorlatinib in the brain. Nine biomarkers related to lorlatinib concentration in the brain were identified. A metabolite-reaction-enzyme-gene interaction network was built to reveal the mechanism of lorlatinib. A multilayer perceptron model based on the identified biomarkers provides a prediction accuracy rate of greater than 85%. The identified biomarkers and the neural network constructed with these metabolites will be valuable for predicting the concentration of drugs in the brain. The model provides a lorlatinib to treat tumor brain metastases in the clinic. |
format | Online Article Text |
id | pubmed-8419651 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-84196512021-09-07 A Comprehensive Analysis of Metabolomics and Transcriptomics Reveals Novel Biomarkers and Mechanistic Insights on Lorlatinib Crosses the Blood-Brain Barrier Chen, Wei Li, Chunyu Shi, Yafei Zhang, Yujun Jin, Dujia Zhang, Mingyu Bo, Mingming Li, Guohui Front Pharmacol Pharmacology Of late, lorlatinib has played an increasingly pivotal role in the treatment of brain metastasis from non-small cell lung cancer. However, its pharmacokinetics in the brain and the mechanism of entry are still controversial. The purpose of this study was to explore the mechanisms of brain penetration by lorlatinib and identify potential biomarkers for the prediction of lorlatinib concentration in the brain. Detection of lorlatinib in lorlatinib-administered mice and control mice was performed using liquid chromatography and mass spectrometry. Metabolomics and transcriptomics were combined to investigate the pathway and relationships between metabolites and genes. Multilayer perceptron was applied to construct an artificial neural network model for prediction of the distribution of lorlatinib in the brain. Nine biomarkers related to lorlatinib concentration in the brain were identified. A metabolite-reaction-enzyme-gene interaction network was built to reveal the mechanism of lorlatinib. A multilayer perceptron model based on the identified biomarkers provides a prediction accuracy rate of greater than 85%. The identified biomarkers and the neural network constructed with these metabolites will be valuable for predicting the concentration of drugs in the brain. The model provides a lorlatinib to treat tumor brain metastases in the clinic. Frontiers Media S.A. 2021-08-23 /pmc/articles/PMC8419651/ /pubmed/34497521 http://dx.doi.org/10.3389/fphar.2021.722627 Text en Copyright © 2021 Chen, Li, Shi, Zhang, Jin, Zhang, Bo and Li. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Chen, Wei Li, Chunyu Shi, Yafei Zhang, Yujun Jin, Dujia Zhang, Mingyu Bo, Mingming Li, Guohui A Comprehensive Analysis of Metabolomics and Transcriptomics Reveals Novel Biomarkers and Mechanistic Insights on Lorlatinib Crosses the Blood-Brain Barrier |
title | A Comprehensive Analysis of Metabolomics and Transcriptomics Reveals Novel Biomarkers and Mechanistic Insights on Lorlatinib Crosses the Blood-Brain Barrier |
title_full | A Comprehensive Analysis of Metabolomics and Transcriptomics Reveals Novel Biomarkers and Mechanistic Insights on Lorlatinib Crosses the Blood-Brain Barrier |
title_fullStr | A Comprehensive Analysis of Metabolomics and Transcriptomics Reveals Novel Biomarkers and Mechanistic Insights on Lorlatinib Crosses the Blood-Brain Barrier |
title_full_unstemmed | A Comprehensive Analysis of Metabolomics and Transcriptomics Reveals Novel Biomarkers and Mechanistic Insights on Lorlatinib Crosses the Blood-Brain Barrier |
title_short | A Comprehensive Analysis of Metabolomics and Transcriptomics Reveals Novel Biomarkers and Mechanistic Insights on Lorlatinib Crosses the Blood-Brain Barrier |
title_sort | comprehensive analysis of metabolomics and transcriptomics reveals novel biomarkers and mechanistic insights on lorlatinib crosses the blood-brain barrier |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419651/ https://www.ncbi.nlm.nih.gov/pubmed/34497521 http://dx.doi.org/10.3389/fphar.2021.722627 |
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