Mohamed W. Attwa, Ali S. Abdelhameed, Adnan A. Kadi
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The precision (%RSD) and accuracy (%E) rates for intra-day and inter-day measurements ranged from −6.33% to 4.91% and −6.67% to 5.26%, respectively. The StarDrop software package involved P450 and Deductive Estimation of Risk from Existing Knowledge modules that were applied for assessing metabolic lability and characterizing ANB structural alarms, respectively. The in vitro half-life (<i>t</i><sub>½</sub>) was computed at 44.72 min, while the clearance intrinsic (Cl<sub>int</sub>) of ANB was calculated at 18.13 mL min<sup>−1</sup> kg<sup>−1</sup>. 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引用次数: 0
摘要
安洛替尼(Focus V)于2018年获得中国药品审评中心批准,作为某些晚期癌症患者的三线治疗药物。本研究旨在建立一种特异、快速、可靠、可持续的超高效液相色谱-串联质谱(UPLC-MS /MS)测定人肝微粒体(HLMs)基质中anlotinib (ANB)的方法,并应用于ANB代谢稳定性的评估。UPLC-MS /MS系统的验证过程符合美国食品和药物管理局关于生物分析方法验证的规定。建立的方法在1分钟内使用HLMs矩阵在1.0至4000 ng mL−1范围内进行验证。日间和日间测量的精密度(%RSD)和准确度(%E)率分别为- 6.33% ~ 4.91%和- 6.67% ~ 5.26%。StarDrop软件包包括P450和现有知识模块的风险演绎估计,分别用于评估代谢不稳定性和表征ANB结构报警。体外半衰期(t½)计算为44.72 min,而ANB的内在清除率(Clint)计算为18.13 mL min−1 kg−1。计算机评估表明,在药物设计中,对甲基(62%)、胺基(37%)和甲氧基(1%)进行轻微的结构改变可能会增加ANB的代谢稳定性。
Evaluation of Anlotinib Metabolic Stability in HLMs Matrix Applying Ultra-Fast UPLC–MS/MS Approach: Greenness Assessment With In Silico Testing for Structural Alarms Related to the Metabolic Lability and DEREK Toxicity
Anlotinib (Focus V) is approved by the China Centre for Drug Evaluation in 2018 as a third-line treatment for patients with certain advanced cancers. This study aimed to develop a specific, fast, reliable, and sustainable ultraperformance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) approach for estimating anlotinib (ANB) in the human liver microsomes (HLMs) matrix, with the application for the assessment of ANB metabolic stability. The validation processes for the UPLC–MS/MS system complied with US Food and Drug Administration regulations following bioanalytical method validation. The established approach was validated using the HLMs matrix over the range of 1.0 to 4000 ng mL−1 within 1 min. The precision (%RSD) and accuracy (%E) rates for intra-day and inter-day measurements ranged from −6.33% to 4.91% and −6.67% to 5.26%, respectively. The StarDrop software package involved P450 and Deductive Estimation of Risk from Existing Knowledge modules that were applied for assessing metabolic lability and characterizing ANB structural alarms, respectively. The in vitro half-life (t½) was computed at 44.72 min, while the clearance intrinsic (Clint) of ANB was calculated at 18.13 mL min−1 kg−1. In silico evaluations suggest that minor structural alterations to the methyl group (62%), amine group (37%), and methoxy group (1%) in drug design may increase the ANB metabolic stability.
期刊介绍:
Biomedical Chromatography is devoted to the publication of original papers on the applications of chromatography and allied techniques in the biological and medical sciences. Research papers and review articles cover the methods and techniques relevant to the separation, identification and determination of substances in biochemistry, biotechnology, molecular biology, cell biology, clinical chemistry, pharmacology and related disciplines. These include the analysis of body fluids, cells and tissues, purification of biologically important compounds, pharmaco-kinetics and sequencing methods using HPLC, GC, HPLC-MS, TLC, paper chromatography, affinity chromatography, gel filtration, electrophoresis and related techniques.