超快速绿色超高效液相色谱-质谱联用法定量人肝微粒体基质中Cediranib的体外和计算机代谢稳定性评价

IF 3.6 3区 医学 Q2 CHEMISTRY, MEDICINAL
Mohamed W. Attwa, Ali S. Abdelhameed, Adnan A. Kadi
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引用次数: 0

摘要

Cediranib (AZD2171; CDB)是一种口服泛vegf受体酪氨酸激酶抑制剂和有效的抗血管生成药物。本研究旨在开发一种精确、快速、可靠和可持续的UPLC-MS/MS方法来测量人肝微粒体(HLM)基质中的CDB,用于评估该基质中CDB的代谢稳定性。UPLC-MS/MS系统的验证过程符合美国fda生物分析技术验证规则。经过验证的方法在UPLC-MS/MS仪器上使用HLM矩阵在1 - 4000 ng/mL的水平范围内持续1分钟。日内和日间测量的精密度(%RSD)和准确度(%E)率分别为- 1.41% ~ 8.0%和- 2.75% ~ 9.67%。StarDrop软件采用P450和DEREK模块分别评估代谢不稳定性和表征CDB结构警告。体外t1/2为25.48 min, CDB固有清除率为31.82 mL/min/kg。计算机评估表明,在药物设计中,对吡咯烷部分(61%)、甲基(32%)和丙基(7%)进行轻微的结构修饰可以提高CDB的代谢稳定性。计算机CDB ADME特性和代谢稳定性的评估是推进以增强代谢稳定性为重点的创新药物研究的基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Ultra-Fast Green UPLC-MS/MS Method for the Quantification of Cediranib in the Human Liver Microsome Matrix: In Vitro and In Silico Metabolic Stability Assessment

Ultra-Fast Green UPLC-MS/MS Method for the Quantification of Cediranib in the Human Liver Microsome Matrix: In Vitro and In Silico Metabolic Stability Assessment

Cediranib (AZD2171; CDB) is an oral pan-VEGF receptor tyrosine kinase inhibitor and a potent antiangiogenic agent. This study sought to develop a precise, rapid, dependable, and sustainable UPLC-MS/MS approach for measuring CDB in the human liver microsome (HLM) matrix, utilized for assessing the CDB metabolic stability inside this matrix. The validation processes for the UPLC-MS/MS system adhered to US-FDA rules for bioanalytical technique validation. The validated method utilized the HLM matrix throughout a level range of 1–4000 ng/mL with a duration of 1 min on UPLC-MS/MS instrumentation. The precision (%RSD) and accuracy (%E) rates for intraday and interday measurements varied from −1.41% to 8.0% and from −2.75% to 9.67%, respectively. The StarDrop software employed P450 and DEREK modules to evaluate metabolic lability and to characterize CDB structural warnings, respectively. The in vitro t1/2 was determined to be 25.48 min, and the CDB intrinsic clearance was determined to be 31.82 mL/min/kg. In silico assessments indicate that slight structural modifications to the pyrrolidine moiety (61%), methyl group (32%), and the propyl group (7%) in drug design could increase the CDB metabolic stability. The assessment of in silico CDB ADME characteristics and metabolic stability is fundamental for progressing innovative drug research focused on augmenting metabolic stability.

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来源期刊
Archiv der Pharmazie
Archiv der Pharmazie 医学-化学综合
CiteScore
7.90
自引率
5.90%
发文量
176
审稿时长
3.0 months
期刊介绍: Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.
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