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Simultaneously measure the concentrations of busulfan and phenytoin in human plasma using an HPLC-MS/MS method: Application to the TDM for children underwent hematological stem cell transplantation

Sun Ning, Li Zhuo, Zhang Meng, He Huan, Zhao Libo, Mei Dong, Zhu Guanghua, Wang Xiaoling

Acta Chromatographica

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2023

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Vol. 35, no. 4

302--309

EN

In this work, a simple and rapid high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method was developed and validated to carry out the simultaneous measurement of busulfan (BU) and phenytoin (PHT) in the plasma of children. In this method, plasma sample could be prepared by one-step protein precipitation using 1 mL of methanol/water (1:1, v/v). After centrifugation (14,500 rpm, 5 min, 4 °C), 10 μL of the supernatant was injected into a Hypersil Gold C18 column (150 × 2.1 mm, 5 μm, Thermo Fisher Scientific) for separation by gradient elution. Quantification was carried out using multiple reactions monitoring (MRM) under positive scan mode. In the method verification, the calibration curves of BU and PHT showed satisfactory linearity (r > 0.99) at the concentration ranging from 0.02 to 20 μg mL⁻¹. The accuracy and precision were tested at four concentration levels (including the LLOQ level) with the relative error (RE) ranging from −0.80% to 11.45% and coefficient of variation (CV) between 0.93% and 7.74%. There was no pronounced matrix effect to interfere with the quantitative analysis. Compared to determine BU and PHT using two individual methods, less pre-treatment process, labor and blood sample volume are required in this proposed method. Finally, this method was successfully applied to the therapeutic drug monitoring of BU and PHT for children underwent hematological stem cell transplantation.

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Simultaneous determination of eight antiepileptic drugs and two metabolites in human plasma by liquid chromatography/tandem mass spectrometry

Yu Hengyi, Ren Xiuhua, Liu Lu, Xiang Dong, Li Xiping, Li Juan, Liu Dong, Gong Xuepeng

Acta Chromatographica

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2023

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Vol. 35, no. 2

161--169

EN

Epilepsy is one of the most prevalent neurological conditions and antiepileptic drugs are the mainstay of epilepsy treatment. High variation in pharmacokinetic profiles of several antiepileptic drugs highlights the importance of therapeutic drug monitoring to estimate pharmacokinetic properties and consequently individualize drug posology. In this work, a simple, rapid and robust liquid chromatography-tandem mass spectrometry method was developed for simultaneous quantification of carbamazepine and its metabolite carbamazepine-10,11-epoxide, gabapentin, levetiracetam, lamotrigine, oxcarbazepine and its metabolite mono-hydroxy-derivative metabolite, phenytoin, topiramate, and valproic acid in human plasma for therapeutic drug monitoring. d6-Levetiracetam, d4-gabapentin and d6-valproic acid were used as internal standards. After addition of internal standards along with two-step protein precipitation and dilution sample preparation, plasma samples were analyzed on a C18 column using a gradient elution in 5 min without interference. The calibration curves were linear over a 100-fold concentration range, with determination coefficients (r2) greater than 0.99 for all analytes. The limit of quantification was 0.5 μg mL⁻¹ (0.1 μg mL⁻¹ for oxcarbazepine, 2 μg mL⁻¹ for levetiracetam, and 10 μg mL⁻¹ for valproic acid) with precision and accuracy ranging from 3% to 9% and from 94% to 112%, respectively. Intra- and inter-day precision and accuracy values were within 15% at low, medium and high quality control levels. No significant matrix effect was observed in the normal, hemolyzed, lipemic, and hyperbilirubin blood samples. This method was successfully used in the identification and quantitation of antiepileptic drugs in patients undergoing mono- or polytherapy for epilepsy.

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LC-MS/MS assay for the therapeutic drug monitoring of perampanel in children with drug-resistant epilepsy

Dai Hao-Ran, Hu Ya-Hui, Long Jia-Yi, Xia Ying, Guo Hong-Li, Xu Jing, Ding Xuan-Sheng, Chen Jing, Lu Xiao-Peng, Chen Feng

Acta Chromatographica

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2023

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Vol. 35, no. 2

149--160

EN

Perampanel (PER) is the first clinically available selective antagonist of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor approved globally for the treatment of epilepsy. Studies have recently underlined the significant association between dose-exposure-effect-adverse events of PER in patients with epilepsy, so the therapeutic drug monitoring (TDM) of PER is critical in clinical practices, especially for pediatric patients with drug-resistant epilepsy. Due to several limits in previous published analytical methods, herein, we describe the development and validation of a novel liquid chromatography tandem mass spectrometry (LC-MS/MS) method for monitoring PER in human plasma samples. Protein precipitation method by acetonitrile containing PER-d5 as internal standard was applied for the sample clean-up. Formic acid (FA, 0.2 mM) in both aqueous water and acetonitrile were used as the mobile phases and the analyte was separated by an isocratic elution. Qualification and quantification were performed under positive electrospray ionization (ESI) mode using the m/z 350.3 → 219.1 and 355.3 → 220.0 ions pairs transitions for PER and PER-d5, respectively. Potential co-medicated anti-seizure medications (ASMs) have no interference to the analysis. Calibration curves were linear in the concentration range of 1.00–2,000 ng mL⁻¹ for PER. The intra- and inter-batch precision, accuracy, recovery, dilution integrity, and stability of the method were all within the acceptable criteria and no matrix effect or carryover was found. This method was then successfully implemented on the TDM of PER in Chinese children with drug-resistant epilepsy. We firstly confirmed the apparent inter- and intra-individual PER concentration variabilities and potential drug-drug interactions between PER and several concomitant ASMs occurred in Chinese pediatric patients, which were also in line with previous studies in patients of other race.

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Analityka antybiotyków β-laktamowych w układzie in silico, in vitro oraz in vivo

Janiszewska Daria, Szultka-Młyńska Małgorzata, Buszewski Bogusław

Wiadomości Chemiczne

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2022

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[Z] 76, 3-4

109--127

EN

Drug analysis necessitates introducing selective methods of detection and enriching the substances present in biomaterial at low concentration levels (trace analysis). Moreover, there is a continuous demand for increase in the quality of drugs that are being developed, which in turn enforces the development of analytical techniques of increasing sensitivity and accuracy with the applicationof combined separation techniques. Thus the premise of this review is to comparethe in vitro metabolic pathways of antibiotic drugs in model conditions such as in the presence of different microsomal fraction enzymes and with the applicationof electrochemical stimulation of metabolic transformations, as well as to the collected data with the results of in vivo experiments.