A Comprehensive Analysis of Metabolomics and Transcriptomics Reveals Novel Biomarkers and Mechanistic Insights on Lorlatinib Crosses the Blood-Brain Barrier

• Main Authors: Wei Chen, Chunyu Li, Yafei Shi, Yujun Zhang, Dujia Jin, Mingyu Zhang, Mingming Bo, Guohui Li
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2021-08-01
• Series: Frontiers in Pharmacology
• Subjects: lorlatinib; metabolomics; transcriptomics; artificial neural network; non-small cell lung cancer
• Online Access: https://www.frontiersin.org/articles/10.3389/fphar.2021.722627/full
• ISSN: 1663-9812

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.