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Pharmacokinetics and metabolism of LNP023 in rats by liquid chromatography combined with electrospray ionization–tandem mass spectrometry
Biomedical Chromatography ( IF 1.8 ) Pub Date : 2020-10-17 , DOI: 10.1002/bmc.5006
Xianglan Jiang 1 , Rongrong Pan 1
Affiliation  

In this study, a simple and sensitive LC–tandem mass spectrometric method was developed and validated for the determination of LNP023 in rat plasma. The plasma sample was precipitated with acetonitrile and then separated on an ACQUITY HSS T3 column (50 mm × 2.1 mm, 1.8 μm) using 0.1% formic acid in water and acetonitrile as the mobile phase. The MS detection was performed in positive multiple‐reaction monitoring mode with precursor‐to‐product ion transitions of m/z 423.3 → 174.1 and m/z 435.3 → 367.1 for LNP023 and olaparib (internal standard), respectively. The developed assay was validated in the linear range of 0.1–1000 ng/mL with correlation coefficient (r) greater than 0.9992. The validation parameters were all within the acceptable limits. The validated method has been successfully used to investigate the pharmacokinetics of LNP023 in rat plasma, and our results indicated that LNP023 showed low clearance and high bioavailability (62.2%). Furthermore, four minor metabolites from rat plasma were detected and identified by LC combined with high‐resolution mass spectrometry. The metabolic pathways were O‐deethylation (M1), hydroxylation (M4), oxidation (M3), and acyl‐glucuronidation (M2).

中文翻译:

液相色谱-电喷雾串联质谱法研究LNP023在大鼠体内的药代动力学

在这项研究中,开发了一种简单而灵敏的LC串联质谱分析方法,并已用于测定大鼠血浆中LNP023的有效性。血浆样品用乙腈沉淀,然后在ACQUITY HSS T 3色谱柱(50 mm×2.1 mm,1.8μm)上分离,使用0.1%甲酸的水溶液和乙腈作为流动相。MS检测是在正向多反应监测模式下进行的,对于LNP023和olaparib(内标),前体-产物离子的跃迁分别为m / z 423.3→174.1和m / z 435.3→367.1。所开发的测定方法在0.1–1000 ng / mL的线性范围内具有相关系数(r)大于0.9992。验证参数均在可接受的范围内。验证的方法已成功用于研究LNP023在大鼠血浆中的药代动力学,我们的结果表明LNP023具有低清除率和高生物利用度(62.2%)。此外,通过液相色谱和高分辨率质谱法检测并鉴定了大鼠血浆中的四种次要代谢物。代谢途径为O-去乙基化(M1),羟基化(M4),氧化(M3)和酰基葡萄糖醛酸化(M2)。
更新日期:2020-10-17
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