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一种超快速超高液相色谱-串联质谱法估算帕博西尼在人肝微粒体中的体外代谢稳定性:用于代谢不稳定性、吸收、分布、代谢和排泄特征的计算研究,以及 DEREK 警示筛选。

An ultra-fast ultra-high-performance liquid chromatography-tandem mass spectrometry method for estimating the in vitro metabolic stability of palbociclib in human liver microsomes: In silico study for metabolic lability, absorption, distribution, metabolism, and excretion features, and DEREK alerts screening.

机构信息

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

出版信息

J Sep Sci. 2024 Aug;47(15):e2400346. doi: 10.1002/jssc.202400346.

Abstract

Palbociclib (Ibrance; Pfizer) was approved for the management of metastatic breast cancer characterized by hormone receptor-positive/human epidermal growth factor receptor 2 negative status. The objective of this study was to create a fast, precise, environmentally friendly, and highly sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry approach for quantifying palbociclib (PAB) in human liver microsomes with the application for assessing metabolic stability. The validation features were performed in agreement with the bioanalytical method validation standards outlined by the US Food and Drug Administration. The StarDrop software (WhichP450 and DEREK modules) was used in screening the metabolic lability and structural alerts of PAB. The separation of PAB and encorafenib (as an internal standard) was achieved on a C8 column, employing an isocratic mobile phase. The inter-day and intra-day accuracy and precision ranged from -6.00% to 4.64% and from -2.33% to 3.13%, respectively. The constructed calibration curve displayed a linearity in the range of 1-3000 ng/mL. The sensitivity of the established approach was proven by the lower limit of quantification of 0.73 ng/mL. The Analytical GREEness calculator results revealed the high level of greenness of the developed method. The PAB's metabolic stability (t of 18.5 min and a moderate clearance (Cl) of 44.8 mL/min/kg) suggests a high extraction ratio medication that matched the WhichP450 software results.

摘要

帕博西尼(爱博新;辉瑞)获批准用于治疗激素受体阳性/人表皮生长因子受体 2 阴性状态的转移性乳腺癌。本研究的目的是建立一种快速、准确、环保且高灵敏度的超高效液相色谱-串联质谱法,用于定量人肝微粒体中的帕博西尼(PAB),并可用于评估其代谢稳定性。验证特征符合美国食品和药物管理局(FDA)概述的生物分析方法验证标准。StarDrop 软件(WhichP450 和 DEREK 模块)用于筛选 PAB 的代谢不稳定性和结构警示。采用等度洗脱方式,在 C8 柱上实现 PAB 与恩考芬尼(作为内标)的分离。日内和日间准确度和精密度的范围分别为-6.00%至 4.64%和-2.33%至 3.13%。构建的校准曲线在 1-3000ng/mL 范围内呈线性。所建立方法的灵敏度通过定量下限(LLOQ)0.73ng/mL 得以证明。Analytical GREEness 计算器的结果显示,所开发方法具有高度的绿色环保特性。PAB 的代谢稳定性(半衰期为 18.5 分钟,清除率(Cl)为 44.8mL/min/kg)表明其为高提取比药物,与 WhichP450 软件的结果一致。

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