BIOMEDICAL CHROMATOGRAPHY
·
2025
·Vol. 39
·期 2
·e6063
·
IF 1.7
Fan Tang,Xiaoli Hou,Jiajie Chen,Yasen Cao,Yixia Wang,Hong Cheng
Mobocertinib is a potent selective tyrosine kinase inhibitor approved for the treatment of non–small cell lung cancer with activating EGFR exon 20 insertions. The aim of this study was to develop a procedure for liquid chromatography tandem mass spectrometry (LC-MS/MS) for the determination of mobocertinib and its metabolite desmethyl-mobocertinib in human plasma. The human plasma samples were precipitated with acetonitrile and analyzed using a Waters ACQUITY BEH C 18 column coupled to a triple quadrupole mass spectrometer. Separation was executed using the acetonitrile–0.1% formic acid solution with gradient elution, at a flow rate of 0.4 mL/min. Mobocertinib and desmethyl-mobocertinib were monitored by multiple reaction monitoring (MRM) with m / z 586.5 > 72.2 and 572.4 > 473.2, respectively. The procedure demonstrated excellent linearity ( r > 0.997) within the concentration range of 0.1–200 ng/mL for both analytes. Precision in relative standard deviation was < 9.37% for mobocertinib and < 12.03% for desmethyl-mobocertinib. Accuracy in relative error was within −7.23% to 9.18% for mobocertinib and −2.78% to 9.87% for desmethyl-mobocertinib. Extraction recovery was > 80% for both analytes. The validated LC-MS/MS method was successfully applied to the pharmacokinetic study of mobocertinib and desmethyl-mobocertinib in healthy human volunteers with K 2 EDTA as anticoagulant after a single dose of mobocertinib (160 mg).
研究领域:
药理学
·
分析化学
·
肿瘤学
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产品关联
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2025
·
IF 4
Dafa Yi,Jiazong Ye,Zebei Lu,Leilei Lu,Tengfei Qi,Tong Luo,Xiuyun Peng,Abdullah Al Mamun,Quan Zhou,Daqing Chen,Shuanghu Wang
This study investigates the potential drug-drug interactions between commonly prescribed anti-hypertensive drugs and mobocertinib in clinical practice to provide the scientific basis for the appropriate therapeutic application of drugs. The study used UPLC-MS/MS to detect the essential metabolites of mobocertinib in rat liver microsomes. Moreover, several anti-hypertensive drugs were used as inhibitors and the IC 50 values were determined for calcium channel blockers, angiotensin II receptor blockers and α and β receptor blockers against mobocertinib. The inhibitory mechanism of mobocertinib was further investigated for nicardipine, irbesartan, telmisartan, carvedilol, prazosin hydrochloride and spironolactone. Twenty-five Sprague Dawley ( SD) rats were randomly divided into five groups: benidipine, nicardipine, telmisartan, irbesartan and blank control groups. The drugs were administered over a period of 7 days. Mobocertinib was administered once by gavage to five groups and then blood samples were collected for further analysis. UPLC-MS/MS was performed to analyze the concentration of mobocertinib and its metabolites in rat plasma. Most anti-hypertensive drugs were found to inhibit the metabolism of mobocertinib in vitro. Several anti-hypertensive drugs were also found to increase the plasma concentration and decrease the metabolic rate of mobocertinib when administered multiple times. More importantly, we found that benidipine, nicardipine, telmisartan and irbesartan inhibited the metabolism of mobocertinib in vitro and in vivo . In summary, our data reveal that anti-hypertensive drugs interact with mobocertinib and additional attention is needed when co-administering the two drugs.
研究领域:
药理学
·
临床医学
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产品关联
DOI
PubMed
高影响因子
Cardiovascular Toxicology
·
2026
·Vol. 26
·期 8
·92
·
IF 3.3
Yan Chi,Liu Xiaohong,Zhang Xiaoyan,Wei Pei,Li Xuefang,Li Dongxu,Zhang Guhao,Li Meng,Zang Xiayan,Lu Guangjian,Lin Fei
Mobocertinib, a tyrosine kinase inhibitor approved for EGFR exon 20 insertion-mutated non-small cell lung cancer, induces cardiotoxicity manifesting as QT prolongation. Salidroside, a bioactive compound from Rhodiola rosea, exhibits cardioprotective properties. We investigated electrophysiological mechanisms underlying mobocertinib cardiotoxicity and salidroside's protective efficacy using Langendorff-perfused rat hearts and neonatal rat cardiomyocytes (NRCMs). Hearts were treated with escalating mobocertinib concentrations (214, 428, 856 nM) with or without salidroside (20 μM) pretreatment; cardiac parameters including heart rate, PR, JT, QTc intervals and conduction were mapped via high-resolution multichannel electrophysiology. NRCMs underwent chronic mobocertinib exposure with/without salidroside, followed by transcriptomic sequencing, qRT-PCR, and western blot validation. Mobocertinib concentration-dependently prolonged PR, JT, QTc intervals, increased conduction time/heterogeneity, reduced heart rate/velocity, and JT/QTc prolongation persisted after washout. Salidroside pretreatment markedly attenuated these abnormalities. In NRCMs, mobocertinib prolonged field potential duration and impaired conduction; salidroside normalized parameters. Transcriptomic analysis identified enrichment in calcium signaling, aldosterone synthesis, cGMP-PKG, and adrenergic pathways. Notably, Atp2b2 was upregulated in mobocertinib group but downregulated in salidroside combination group, whereas Agtr1b showed opposite pattern. Thus, salidroside mitigates mobocertinib-induced electrophysiological toxicity by modulating Atp2b2/Agtr1b-related signaling networks, providing a novel cardioprotective strategy against mobocertinib-associated cardiotoxicity. Graphical
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产品关联
DOI
高影响因子
TOXICOLOGY
·
2024
·
IF 4.8
Wenting Wu,Jinglei Sun,Jiali Zhang,Haining Zhao,Suhua Qiu,Congxin Li,Chenxia Shi,Yanfang Xu
The use of tyrosine kinase inhibitors (TKIs) has resulted in significant occurrence of arrhythmias. However, the precise mechanism of the proarrhythmic effect is not fully understood. In this study, we found that nilotinib (NIL), vandetanib (VAN), and mobocertinib (MOB) induced the development of “cellrhythmia” (arrhythmia-like events) in a concentration-dependent manner in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Continuous administration of NIL, VAN, or MOB in animals significantly prolonged the action potential durations (APD) and increased susceptibility to arrhythmias. Using phosphoproteomic analysis, we identified proteins with altered phosphorylation levels after treatment with 3 μM NIL, VAN, and MOB for 1.5 h. Using these identified proteins as substrates, we performed kinase–substrate enrichment analysis to identify the kinases driving the changes in phosphorylation levels of these proteins. MAPK and WNK were both inhibited by NIL, VAN, and MOB. A selective inhibitor of WNK1, WNK-IN-11, induced concentration- and time-dependent cellrhythmias and prolonged field potential duration (FPD) in hiPSC-CMs in vitro; furthermore, administration in guinea pigs confirmed that WNK-IN-11 prolonged ventricular repolarization and increased susceptibility to arrhythmias. Fingding indicated that WNK1 inhibition had an in vivo and in vitro arrhythmogenic phenotype similar to TKIs. Additionally,three of TKIs reduced hERG and KCNQ1 expression at protein level, not at transcription level. Similarly, the knockdown of WNK1 decreased hERG and KCNQ1 protein expression in hiPSC-CMs. Collectively, our data suggest that the proarrhythmic effects of NIL, VAN, and MOB occur through a kinase inhibition mechanism. NIL, VAN, and MOB inhibit WNK1 kinase, leading to a decrease in hERG and KCNQ1 protein expression, thereby prolonging action potential repolarization and consequently cause arrhythmias.
研究领域:
心脏病学
·
药理学
·
蛋白质组学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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