Drug Design Development and Therapy
·
2026
·
IF 6.1
Na Yang,Yuqing Zhao,Shiyu Liu,Yifan Zhou,Xinyue Ji,Tianqi Zhang,Runbin Sun,Huaijun Zhu,Yao Du,Min Wang
Background Mycophenolic acid (MPA), administered as mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS), is the first-line immunosuppressant for kidney transplant patients. Traditional plasma-based therapeutic drug monitoring (TDM) for MPA fails to accurately reflect intracellular drug exposure at the pharmacological action site.Purpose This study aimed to establish and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of MPA and its glucuronide metabolite, MPAG, in peripheral blood mononuclear cells (PBMCs) to support cellular pharmacokinetic (PK) assessment.Methods Chromatographic separation was performed on a BEH C18 column using methanol-water containing 0.1% formic acid and 5 mmol/L ammonium acetate. A total of 139 PBMC samples from 40 kidney transplant recipients (n=19 receiving EC-MPS; n=21 receiving MMF) were analyzed to evaluate the plasma-PBMC PK correlations and gender-related differences.Results The method exhibited excellent linearity over the concentration range of 0.2–500 ng/mL (R2 > 0.998), along with acceptable precision, accuracy and matrix effect. The analytes remained stable under various experimental conditions. Significant inter-individual variability in intracellular MPA and MPAG concentrations was observed among patients. Spearman correlation analysis demonstrated a weak-to-moderate positive correlation between plasma and intracellular PBMC concentrations of MPA (EC-MPS, Rs=0.396; MMF, Rs=0.480). Additionally, the concentration-time profiles of MPA and MPAG in PBMCs of kidney transplant recipients after administration of EC-MPS or MMF exhibited different characteristics. No significant gender-based differences in plasma and PBMCs were observed.Conclusion We established and validated an LC-MS/MS method for simultaneous quantification of intracellular MPA and MPAG. The observed weak-to-moderate correlation between plasma and PBMC exposure highlights the inherent limitations of conventional plasma-based TDM for MPA. Collectively, our study provides a feasible approach for monitoring intracellular drug levels and facilitates the optimization of individualized immunosuppressive dosing regimens for renal transplant recipients.
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JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
·
2026
·
IF 2.5
Yagang Li,Shuyan Huo,Yunhui Xing,Yonghang He,Wei Wu,Min Huang,Yiming Jiang,Guoping Zhong,Weiwei Zeng
Novel TiO 2 @MWCNTs composites were designed and synthesized, which exhibit potential as purification materials for phospholipid removal from rat plasma samples. • A dispersive solid-phase extraction method based on TiO 2 @MWCNTs showed the capacity to mitigate matrix effects in rat plasma samples for small-molecule analytes with low lg P . • An LC–MS/MS method was established and validated for quantifying representative drugs using TiO 2 @MWCNTs and applied to a pharmacokinetic study of metformin. The matrix effect is a prevalent interference in LC–MS/MS bioanalysis of small-molecule drugs, with lipids as a major source of such interference in plasma matrices. Leveraging the lipid-adsorbing capability of multi-walled carbon nanotubes (MWCNTs), this study synthesized TiO 2 @MWCNTs composites and developed a novel dispersive solid-phase extraction (d-SPE) method to reduce matrix effects in rat plasma. Lipid profiles were compared to characterize the lipid purification capacity of TiO 2 @MWCNTs in rat plasma samples. The matrix effects of representative small-molecule drugs, including metformin, amisulpride, and aripiprazole, were compared across TiO 2 @MWCNTs-based d-SPE, protein precipitation, and traditional solid-phase extraction. Method validation and sample determination were subsequently performed. The results demonstrated that TiO 2 could be successfully loaded onto MWCNTs. The responses of 72 differential lipid ions were significantly reduced by at least 2-fold after TiO 2 @MWCNTs treatment, and the IS-normalized matrix factors for metformin (from 13.69 to 20.00% to 31.49–44.39%) and amisulpride (from 71.01 to 84.82% to 91.69–101.48%) as well as accuracy for aripiprazole at low concentration were significantly improved compared with protein precipitation treatment. Method validation results confirmed excellent selectivity, accuracy, precision, and reproducibility. The validated method was also successfully applied to a pharmacokinetic study of metformin with pharmacokinetic parameters comparable to those reported previously. This study shows that the dispersive solid-phase extraction method based on TiO 2 @MWCNTs could act as a simple, rapid, low-cost and reliable pretreatment strategy to mitigate matrix effects for small-molecule analytes with low lg P in rat plasma as a proof-of-concept attempt.
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TALANTA
·
2026
·
IF 6.7
Lei Ding,Ruochen Zhang,Wenchan Deng,Feifei Chen,Shuangshuang Liu,Jinsheng Lin,Cuirong Sun
Vericiguat (VER), a novel soluble guanylate cyclase agonist for heart failure, was subjected to comprehensive forced degradation studies to assess its stability and elucidate degradation pathways. The study was conducted in accordance with ICH guidelines, including alkaline, acidic, oxidative, photolytic, and thermal stress conditions. And tentatively structural identification of degradation impurities was carried out using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). The results indicated that VER was susceptible to degradation under alkaline (NaOH) and hydrogen peroxide (H 2 O 2 ) oxidative conditions, yielding nine degradation impurities (DIs 1-7, 9, 10). Among these, eight have not been previously reported, with the exception of DI-7. Moreover, under a newly introduced free-radical oxidation condition using benzoyl peroxide (BPO), two additional novel impurities (DI-8 and DI-11) were generated. And two major degradants (DI-3-2 and DI-5) were isolated and their structures were confirmed by 1Dimension/2Dimension-Nuclear Magnetic Resonance (1D/2D-NMR) analysis. Based on the structures of the degradation impurities, the degradation pathways were elucidated and the molecular stability was investigated. The results demonstrate that the primary degradation mechanisms involved pyrimidine ring cleavage, oxidation of the amino group, hydrolysis of ester and amide bonds, as well as intramolecular cyclization and rearrangement. This study successfully established a comprehensive impurity profile for VER and provided robust scientific data for formulating its quality standards, thereby supporting stability assessment and quality control during pharmaceutical development.
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JOURNAL OF MASS SPECTROMETRY
·
2026
·Vol. 61
·期 5
·e70059
·
IF 2.1
Yongjuan Jia,Xingli Liu,Yongmei Chen,Wei Li
Comprehensive profiling of sex steroid hormones (SSHs) is of great significance for elucidating the pathogenesis of SSHs-related diseases. However, it is challenging because of the low endogenous abundance and the presence of multiple analytes with similar structures and isomers. In this study, we developed a simple, rapid, and clinically transferable method for the profiling of 28 SSHs in human serum samples. After liquid–liquid extraction, the serum samples were directly detected by liquid chromatography–tandem mass spectrometry. Twenty-three isomers or structural analogues were separated on Kinetex F5 column within 14 min. Good linearities were achieved in the quantitative range for each analyte with the regression coefficients R 2 > 0.99088. The limits of quantitation of the method were in the range from 0.005 to 1 ng/mL. The recoveries were in the range of 90.4%–107.9% with the intraday and interday precisions within 14.35%. This method had been successfully applied for the determination of SSHs in human serum samples with simple operation and good accuracy and could provide a viable approach for clinical screening of SSHs.
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MOLECULES
·
2025
·Vol. 30
·期 7
·1404
·
IF 4.6
Qingling Xie,Hanwen Yuan,Shiqi Liu,Ling Liang,Jiangyi Luo,Mengyun Wang,Bin Li,Wei Wang
Forsythia suspensais a crucial plant resource due to its considerable edible and medicinal value. Its fruit, named Forsythiae Fructus (FF), has been widely used in Traditional Chinese Medicine (TCM). According to the fruit maturity stage, FF is categorized into GFF (green Forsythiae Fructus) and RFF (ripe Forsythiae Fructus). In this study, metabolomics based on UPLC-Q/Orbitrap MS and HS-GC-MS, combined with chemometric methods, was employed to differentiate GFF from RFF and identify potential differential metabolites. Additionally, the mid-level data fusion method was employed to integrate data from both techniques, and the performance of the OPLS-DA model (R2Y = 0.986, Q2= 0.974) surpassed that of the single HS-GC-MS technique (R2Y = 0.968, Q2= 0.930). Moreover, using the criteria of VIP > 1 andp-value < 0.05, 30 differential compounds were selected via mid-level data fusion, compared to the initial 61 differential compounds identified by single techniques, effectively reducing data noise and eliminating irrelevant variables. This study provides a comprehensive analysis of volatile and non-volatile compounds in FF, offering valuable insights into quality control and clinical differentiation between GFF and RFF. The findings highlight the potential use of multi-technology metabolomics in the quality control of TCM and offer new perspectives for future research on medicinal plants.
研究领域:
中药学
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分析化学
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TALANTA
·
2024
·
IF 5.6
Jie Han,Qinyan Yang,Zheng Zhi,Na Li,Jian-Lin Wu
Carboxyl: or carbonyl-containing metabolites (CoCCMs) are widely distributed in biological samples. Global profiling of CoCCMs is essential for ascertaining specific functions of metabolites and their potential physiological roles in biogenic activities. However, simultaneous determination of these compounds is hampered by poor ionization efficiency, vast polarity differences, wide discrepancy of concentration ranges. Herein, a novel bromine isotope derivatization reagent 5-bromo-2- hydrazinopyridine was employed for CoCCMs profiling by liquid chromatography-mass spectrometry (LC-MS). This method enabled rapid derivatization of 44 CoCCMs under mild conditions. Enhanced separation efficiencies, detection sensitivities, and distinctive MS fragmentation characteristics were observed. Furthermore, this method was demonstrated to be efficient in revealing metabolic alternations, and abnormal serum levels of 6-keto-PGF1α, 12(S)-HHTrE, 15(S)-HEPE and N -acetyl tryptophan were disclosed for the first time in Mycoplasma pneumoniae (MP) infectious patients. Finally, based on the distinctive 2 Da differences of molecular ion peak pairs with almost 1:1 intensity ratio originated from 79 Br and 81 Br isotopes, an MS-DIAL and Python assisted MS1 isotope screening-MS2 fragments characterization combination strategy was developed for rapid screening, classification, and identification of detected CoCCMs. A total of 1,069 CoCCMs were detected, of which 198 CoCCMs were identified in untargeted analysis. Statistical analysis revealed altered metabolic pathways, while glutamic acid, oxoglutaric acid, succinic acid, pyruvic acid, glyceric acid, and glycine were selected as potential biomarkers of MP infection. This bromine signature coded derivatization-LC-MS approach was proved to be a valuable tool for global probing of CoCCMs in biological samples with high sensitivity and broad coverage.
研究领域:
医学
·
生物化学
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METHODS
·
2024
·
IF 4.2
Sisi Gong,Qingshui Wang,Jiewei Huang,Rongfu Huang,Shanshan Chen,Xiaojuan Cheng,Lei Liu,Xiaofang Dai,Yameng Zhong,Chunmei Fan,Zhijun Liao
Background Breast cancer (BC), the most common form of malignant cancer affecting women worldwide, was characterized by heterogeneous metabolic disorder and lack of effective biomarkers for diagnosis. The purpose of this study is to search for reliable metabolite biomarkers of BC as well as triple-negative breast cancer (TNBC) using serum metabolomics approach. Methods In this study, an untargeted metabolomics technique based on ultra-high performance liquid chromatography combined with mass spectrometry (UHPLC-MS) was utilized to investigate the differences in serum metabolic profile between the BC group (n = 53) and non-BC group (n = 57), as well as between TNBC patients (n = 23) and non-TNBC subjects (n = 30). The multivariate data analysis, determination of the fold change and the Mann-Whitney U test were used to screen out the differential metabolites. Additionally, machine learning methods including receiver operating curve analysis and logistic regression analysis were conducted to establish diagnostic biomarker panels. Results There were 36 metabolites found to be significantly different between BC and non-BC groups, and 12 metabolites discovered to be significantly different between TNBC and non-TNBC patients. Results also showed that four metabolites, including N-acetyl-D-tryptophan, 2-arachidonoylglycerol, pipecolic acid and oxoglutaric acid, were considered as vital biomarkers for the diagnosis of BC and non-BC with an area under the curve (AUC) of 0.995. Another two-metabolite panel of N-acetyl-D-tryptophan and 2-arachidonoylglycerol was discovered to discriminate TNBC from non-TNBC and produced an AUC of 0.965. Conclusion This study demonstrated that serum metabolomics can be used to identify BC specifically and identified promising serum metabolic markers for TNBC diagnosis.
研究领域:
肿瘤学
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代谢组学
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生物信息学
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临床诊断
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Toxics
·
2025
·Vol. 13
·期 5
·352
·
IF 4.1
Yubing Yan,Bowen Liang,Jiawen Yang,Qing Deng,Xiaoying Liang,Hui Chen,Bibai Du,Lixi Zeng
Fluorescent brighteners (FBs) are a class of chemicals extensively used in industrial and consumer products. Their environmental occurrences and potential health risks have raised significant concerns. However, the lack of analytical methods for FBs in human samples has hindered the accurate assessment of internal exposure levels. Addressing this gap, this study developed and validated a novel method for the simultaneous determination of 13 FBs at trace levels in human plasma using solid-phase extraction combined with HPLC-MS/MS. The method employed EMR-Lipid SPE columns, which can selectively adsorb phospholipids for plasma sample pre-treatment. Detection was achieved through positive ion electrospray ionization (ESI) in multiple reaction monitoring (MRM) modes. The results showed that all 13 FBs exhibited good linearity within their respective ranges, with correlation coefficients (R2) greater than 0.992. The method quantitation limits (MQLs) of the FBs ranged from 0.012 to 0.348 ng/mL, and the spiked recovery rates ranged from 61% to 98%. The method was successfully applied to analyze 10 adult plasma samples, detecting 10 FBs with total concentrations ranging from 0.221 to 0.684 ng/mL. This study provides a reliable analytical method for determining FBs in human plasma, providing a basis for further research on human internal exposure to FBs and associated health risk assessments.
研究领域:
分析化学
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环境健康学
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毒理学
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JOURNAL OF LIPID RESEARCH
·
2020
·Vol. 61
·期 4
·580-586
·
IF 4.483
Teng-Fei Yuan (袁;腾;飞,Juan Le (乐;娟,Shao-Ting Wang (王;少;亭,Yan Li (李;艳
Analyzing global steroid metabolism in humans can shed light on the etiologies of steroid-related diseases. However, existing methods require large amounts of serum and lack the evaluation of accuracy. Here, we developed an LC/MS/MS method for the simultaneous quantification of 12 steroid hormones: testosterone, pregnenolone, progesterone, androstenedione, corticosterone, 11-deoxycortisol, cortisol, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone, estriol, and estradiol. Steroids and spiked internal standards in 100 μl serum were extracted by protein precipitation and liquid-liquid extraction. The organic phase was dried by evaporation, and isonicotinoyl chloride was added for steroid derivatization, followed by evaporation under nitrogen and redissolution in 50% methanol. Chromatographic separation was performed on a reverse-phase PFP column, and analytes were detected on a triple quadrupole mass spectrometer with ESI. The lower limits of quantification ranged from 0.005 ng/ml for estradiol to 1 ng/ml for cortisol. Apparent recoveries of steroids at high, medium, and low concentrations in quality control samples were between 86.4% and 115.0%. There were limited biases (−10.7% to 10.5%) between the measured values and the authentic values, indicating that the method has excellent reliability. An analysis of the steroid metabolome in pregnant women highlighted the applicability of the method in clinical serum samples. We conclude that the LC/MS/MS method reported here enables steroid metabolome analysis with high accuracy and reduced serum consumption, indicating that it may be a useful tool in both clinical and scientific laboratory research.
研究领域:
临床医学
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分析化学
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高影响因子
Scientific Reports
·
2025
·Vol. 15
·期 1
·1-8
·
IF 3.9
Liu Hao,Cai Meng,Peng Yong,Miao Jing-kun,Yu Jin
While remifentanil, etomidate, and rocuronium are increasingly used for cesarean section due to their favorable hemodynamic stability and fetal safety profile, their pharmacokinetics and potential effects on neonates remain poorly understood. This study developed and validated a rapid, sensitive LC–MS/MS method for simultaneous quantification of the three anesthetics in microsamples of 10 μl serum, followed by a paired maternal and umbilical cord serum investigation. After protein precipitation with acetonitrile, analytes were separated within 4 min using positive electrospray ionization in MRM mode. Method validation demonstrated excellent linearity (R 2 > 0.99) for all compounds, with LLOQs of 0.15 ± 0.02 ng/mL (remifentanil), 16.87 ± 0.51 ng/mL (etomidate), and 106.73 ± 8.63 ng/mL (rocuronium). Precision (intra-/inter-day < 15%) and minimal carry-over (< 5%) met bioanalytical standards. Applied to 20 maternal-newborn pairs, the method quantified differential drug distribution: maternal arterial concentrations (remifentanil 4.75 ± 0.19 ng/mL; etomidate 412.71 ± 35.29 ng/mL; rocuronium 7.08 ± 0.48 μg/mL) exceeded umbilical vein levels (2.43 ± 0.13 ng/mL; 302.15 ± 29.03 ng/mL; 0.86 ± 0.16 μg/mL), which were higher than umbilical artery concentrations (1.33 ± 0.15 ng/mL; 166.24 ± 21.53 ng/mL; 0.44 ± 0.77 μg/mL). Calculated placental transfer rates significantly differed among anesthetics (remifentanil 0.52 ± 0.02; etomidate 0.75 ± 0.04; rocuronium 0.13 ± 0.02; all P < 0.001), reflecting distinct pharmacokinetic behaviors. The validated method enables reliable microvolume analysis for perinatal pharmacokinetic studies, particularly valuable when sample availability is limited. Its rapid throughput and sensitivity make it suitable for clinical research applications investigating maternal–fetal drug transfer dynamics.
研究领域:
分析化学
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药代动力学
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麻醉学
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妇产科学
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新生儿学
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临床研究
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ANALYTICA CHIMICA ACTA
·
2025
·
IF 6
Shiwen Zhou,He Tang,Lu Gao,Wangyu Li,Jiancong Liao,Xihe Yang,Yuanjiang Pan,Hongru Feng
Background Oligonucleotide-based drugs have gained significant attention as a promising class of therapeutics due to their precise ability to regulate gene expression. However, the presence of impurities in these drugs can compromise their safety, efficacy, and stability. Therefore, the identification and detailed analysis of these impurities are crucial. Traditional methods may struggle to detect subtle impurities, such as oxidation and hydrolysis products, which necessitate the development of more advanced and reliable analytical techniques for oligonucleotide therapeutics. Results In this study, we introduce a novel analytical method that combines heart-cutting two-dimensional liquid chromatography (2D-LC) with tandem mass spectrometry (MS/MS) to effectively separate, analyze, and identify impurities in oligonucleotide-based drugs. The first dimension utilizes anion exchange chromatography (AEX) to separate oligonucleotides based on their negative charge, while the second dimension employs reverse ion-pair chromatography (RIPC) for further purification and compatibility with mass spectrometry. This 2D-LC-MS/MS approach provides a sensitive and accurate means of identifying and quantifying impurities, including oxidation and hydrolysis products. The method was applied to two RNA interference (RNAi) drugs, Givosiran and Patisiran, where 3 and 20 impurities were identified, respectively. Additionally, sequencing analysis using data-dependent acquisition (DDA-MS/MS) enabled the determination of the molecular weight and structural characteristics of these impurities, offering a comprehensive and detailed view of the impurity profiles. Significance This novel heart-cutting 2D-LC-MS/MS method offers a significant advancement in the analysis of impurities in oligonucleotide-based therapeutics. It provides high sensitivity, enabling the identification of subtle impurities that are often challenging to detect. By applying this technique to RNAi drugs, we demonstrate its potential to enhance the safety, efficacy, and stability of oligonucleotide-based therapies, making it a valuable tool for the pharmaceutical industry.
研究领域:
药物分析
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分析化学
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生物治疗学
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质谱分析
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色谱分析
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药物研发
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生物药剂学
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高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 7
·3654
·
IF 4.9
Wencheng Zhao,Huizi Cui,Kaifeng Liu,Xiaotang Yang,Shu Xing,Wannan Li
Type 2 diabetes mellitus (T2DM) is marked by persistent hyperglycemia, insulin resistance, and pancreatic β-cell dysfunction, imposing substantial health burdens and elevating the risk of systemic complications and cardiovascular diseases. While the pathogenesis of diabetes remains elusive, a cyclical relationship between insulin resistance and inflammation is acknowledged, wherein inflammation exacerbates insulin resistance, perpetuating a deleterious cycle. Consequently, anti-inflammatory interventions offer a therapeutic avenue for T2DM management. In this study, a herb called Baikal skullcap, renowned for its repertoire of bioactive compounds with anti-inflammatory potential, is posited as a promising source for novel T2DM therapeutic strategies. Our study probed the anti-diabetic properties of compounds from Baikal skullcap via network pharmacology, molecular docking, and cellular assays, concentrating on their dual modulatory effects on diabetes through Protein Tyrosine Phosphatase 1B (PTP1B) enzyme inhibition and anti-inflammatory actions. We identified the major compounds in Baikal skullcap using liquid chromatography–mass spectrometry (LC–MS), highlighting six flavonoids, including the well-studied baicalein, as potent inhibitors of PTP1B. Furthermore, cellular experiments revealed that baicalin and baicalein exhibited enhanced anti-inflammatory responses compared to the active constituents of licorice, a known anti-inflammatory agent in TCM. Our findings confirmed that baicalin and baicalein mitigate diabetes via two distinct pathways: PTP1B inhibition and anti-inflammatory effects. Additionally, we have identified six flavonoid molecules with substantial potential for drug development, thereby augmenting the T2DM pharmacotherapeutic arsenal and promoting the integration of herb-derived treatments into modern pharmacology.
研究领域:
药理学
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糖尿病研究
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草药医学
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生物化学
·
分子生物学
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