In the clinic, ethosuximide is commonly used to treat generalized absence seizures but has recently been repurposed for other diseases. Because of adverse effects and drug interactions, high-throughput therapeutic drug monitoring of ethosuximide is necessary. Microextraction is a simple, effective, rapid, and low consumption of organic solvents method for sample preparation. In this study, microderivatization-increased detection (MDID)-combined microextraction was used to detect ethosuximide by mass spectrometry. Ethosuximide is a difficult to retain and ionize compound in the C18 nano-flow column and ionization interface, respectively. Hence, we developed a fast method for detecting ethosuximide in human plasma by using the MDID strategy (within 2 min). Chemical microderivatization parameters were studied and optimized to increase the sensitivity of ethosuximide detection at trace levels. The linear range for the analysis of ethosuximide in 10 μL plasma was 5-500 μg/mL with a coefficient of determination (r) ≥ 0.995. The precision and accuracy of intraday and interday analyses of ethosuximide were below 13.0%. Furthermore, modifications of major proteins in plasma and blood cells, induced by ethosuximide, were identified. The proposed method effectively utilizes microliter samples to detect drug plasma concentrations under suitable microextraction procedures toward the eco-friendly goal of low consumption of organic solvents. Graphical abstract ᅟ.
Rationale Understanding drug–drug interactions and predicting the side effects induced by polypharmacy are difficult because there are few suitable platforms that can predict drug–drug interactions and possible side effects. Hence, developing a platform to identify significant protein markers of drug–drug interactions and their associated side effects is necessary to avoid adverse effects. Methods Human liver cells were treated with ethosuximide in combination with cimetidine, ketotifen, metformin, metronidazole, or phenytoin. After sample preparation and extraction, mitochondrial proteins from liver cells were isolated and digested with trypsin. Then, peptide solutions were detected using a nano ultra‐performance liquid chromatographic system combined with tandem mass spectrometry. The Ingenuity Pathway Analysis tool was used to simulate drug–drug interactions and identify protein markers associated with drug‐induced adverse effects. Results Several protein markers were identified by the proposed method after liver cells were co‐treated with ethosuximide and other drugs. Several of these protein markers have previously been reported in the literature, indicating that the proposed platform is workable. Conclusions Using the proposed in vitro platform, significant protein markers of drug–drug interactions could be identified by mass spectrometry. This workflow can then help predict indicators of drug–drug interactions and associated adverse effects for increased safety in clinical prescriptions.
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