Liquid Chromatography Combined With Electrospray Ionization Tandem Mass Spectrometry for the Determination and Identification of AZD5462 and Its Metabolites in Rat Plasma

IF 1.8 4区医学 Q4 BIOCHEMICAL RESEARCH METHODS

Biomedical Chromatography Pub Date : 2025-04-25 DOI:10.1002/bmc.70095

Congyao You, Yan Zhang, Dece Kong, Tieyi Yang

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引用次数: 0

Abstract

AZD5462, a human RXFP1 agonist, which is undergoing clinical development for the treatment of heart failure. The aim of this study was to develop an ultra-high-performance liquid chromatography-tandem mass spectrometric method for the determination of AZD5462 in rat plasma. After precipitated with acetonitrile, the sample was analyzed on a BEH C₁₈ column using 0.1% formic acid and acetonitrile as mobile phase with a gradient elution at 40°C within 2 min. The assay showed excellent linearity in the range of 0.1–1000 ng/mL with the correlation coefficient more than 0.995. The precision, accuracy, matrix effect, recovery, and stability met all requirements for the quantitation in plasma samples. The validated method has been further applied to the pharmacokinetic study of AZD5462 in rats. In addition, the metabolism of AZD5462 in rat was investigated by a liquid chromatography-high resolution mass spectrometry. In rat liver microsomes, four metabolites were identified based on their accurate mass and fragment ions. In rat plasma, one glucuronide conjugate was identified. The metabolic pathways of AZD5462 include oxygenation and glucuronidation. This study is the first report on the pharmacokinetics and metabolism of AZD5462, which would provide insights into the effectiveness and toxicity of this drug candidate.

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液相色谱-电喷雾串联质谱联用测定大鼠血浆中AZD5462及其代谢物

AZD5462，一种人类RXFP1激动剂，正在进行临床开发，用于治疗心力衰竭。建立了一种超高效液相色谱-串联质谱法测定大鼠血浆中AZD5462的方法。用乙腈沉淀后，在BEH C18色谱柱上分析，流动相为0.1%甲酸和乙腈，40℃梯度洗脱，2 min。在0.1 ~ 1000 ng/mL范围内线性良好，相关系数大于0.995。精密度、准确度、基质效应、回收率、稳定性均满足血浆样品定量的要求。将验证的方法进一步应用于AZD5462在大鼠体内的药代动力学研究。此外，采用液相色谱-高分辨质谱法研究了AZD5462在大鼠体内的代谢。在大鼠肝微粒体中，根据其精确的质量和碎片离子鉴定了四种代谢物。在大鼠血浆中鉴定出一种葡萄糖醛酸缀合物。AZD5462的代谢途径包括氧合和葡萄糖醛酸化。本研究首次报道了AZD5462的药代动力学和代谢特性，有助于进一步了解该候选药物的有效性和毒性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biomedical Chromatography 生物-分析化学

CiteScore

3.60

自引率

5.60%

发文量

268

审稿时长

2.3 months

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.