液相色谱-光电二极管阵列-质谱法分离抗癌药物富马酸吉尔替尼氧化降解产物

IF 1 4区 化学 Q4 CHEMISTRY, ANALYTICAL
Pushpa Pilli, Sowmya Chaganti, Vijaya Madhyanapu Golla, Hema Sree Kommalapati, Bhukya Vijay Nayak, Gananadhamu Samanthula
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引用次数: 0

摘要

Gilteritinib (GTB)用于治疗难治性或复发性急性髓系白血病,并抑制几种受体酪氨酸激酶,包括fms样酪氨酸激酶3和AXL。本研究的主要目的是根据ICH Q1A和Q1B标准确定GTB在强制条件下(水解、氧化和光解)的降解情况。在进行研究之前,使用Zeneth软件预测GTB的计算机退化概况。发现GTB在水解(酸性、碱性和中性)和光解条件下稳定,但在氧化(H2O2)条件下不稳定,产生三种新的降解产物。降解产物采用Phenomenex Gemini C18色谱柱(250 × 4.6 mm, 5µm),在反相高效液相色谱梯度程序中进行鉴定和分离。流动相为10 mM甲酸铵加0.01%醋酸(pH未调整,%A)和甲醇(%B)。采用高分辨率质谱法对降解产物进行结构解析。所得数据使我们能够提出一种降解产物形成的机制。利用计算机技术(DEREK Nexus、SARAH Nexus和ProTox-3.0)对GTB及其降解产物的毒性和诱变性进行了预测。总之,本研究强调了GTB的安全监测和储存条件。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Separation of Oxidative Degradation Products of the Anti-Cancer Drug Gilteritinib Fumarate by Liquid Chromatography with Photodiode Array and Mass Spectrometric Detection

Gilteritinib (GTB) is used for the treatment of refractory or relapsed acute myeloid leukemia and inhibits several receptor tyrosine kinases, including FMS-like tyrosine kinase 3 and AXL. The main objective of the current study was to determine how GTB degrades under forced conditions (hydrolysis, oxidation, and photolysis) in accordance with ICH Q1A and Q1B criteria. Zeneth software was used to predict the in-silico deterioration profile of GTB before the study was carried out. GTB was found to be stable under hydrolytic (acidic, basic, and neutral) and photolytic degradation conditions, but it was labile under oxidative (H2O2) conditions, producing three novel degradation products. The degradation products were identified and separated using a Phenomenex Gemini C18 column (250 × 4.6 mm, 5 µm) in a reversed-phase high-performance liquid chromatography with a gradient program. Mobile phases consisted of 10 mM ammonium formate with 0.01% acetic acid (pH unadjusted, %A) and methanol (%B). High-resolution mass spectrometry was used for the structural elucidation of the degradation products. The resulting data enabled the proposal of a mechanism for the formation of the degradation products. Using in silico techniques (DEREK Nexus, SARAH Nexus, and ProTox-3.0), the toxicity and mutagenicity of GTB and its degradation products were predicted. In summary, this study highlights safety monitoring and storage conditions for GTB.

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来源期刊
Journal of Analytical Chemistry
Journal of Analytical Chemistry 化学-分析化学
CiteScore
2.10
自引率
9.10%
发文量
146
审稿时长
13 months
期刊介绍: The Journal of Analytical Chemistry is an international peer reviewed journal that covers theoretical and applied aspects of analytical chemistry; it informs the reader about new achievements in analytical methods, instruments and reagents. Ample space is devoted to problems arising in the analysis of vital media such as water and air. Consideration is given to the detection and determination of metal ions, anions, and various organic substances. The journal welcomes manuscripts from all countries in the English or Russian language.
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