Optimization of a sensitive and reliable UPLC-MS/MS method to simultaneously quantify almonertinib and HAS-719 and its application to study the interaction with nicardipine.

IF 3.9 3区医学 Q1 MEDICAL LABORATORY TECHNOLOGY Pharmaceutical Biology Pub Date : 2024-12-01 Epub Date: 2024-11-14 DOI:10.1080/13880209.2024.2425648

Dongxin Chen, Jie Chen, Yuxin Shen, Xiaohai Chen, Hailun Xia, Ya-Nan Liu, Ren-Ai Xu

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Abstract

Context: Almonertinib is primarily metabolized by CYP3A4, so it could interact with a variety of drugs metabolized by CYP3A4, leading to the changes of systemic exposure.

Objective: For the purpose of this experiment, an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay with accuracy and simplicity was optimized and fully validated for the simultaneous quantitative determination of almonertinib and its metabolite HAS-719, and drug-drug interactions (DDI) between almonertinib and nicardipine in vivo and in vitro was researched.

Materials and methods: Detection of analytes was achieved by UPLC-MS/MS coupled with multiple reaction monitoring (MRM) in the positive ion mode with ion transitions of m/z 526.01 → 72.04 for almonertinib, m/z 512.18 → 455.08 for HAS-719 and m/z 447.16 → 128.11 for IS, respectively.

Results: There was favourable linearity in the 0.5-200 ng/mL calibration range for almonertinib and 0.5-100 ng/mL for HAS-719. The lower limit of quantification (LLOQ) for both analytes was 0.5 ng/mL. The precision, accuracy, stability, matrix effect and extraction recovery required for methodological validation were consistent with the requirements of FDA guideline. Then, the UPLC-MS/MS assay was employed successfully on the interactions of almonertinib and nicardipine in vivo and in vitro. The half-maximal inhibitory concentration (IC₅₀) was 1.19 μM in rat liver microsomes (RLM), where nicardipine inhibited the metabolism of almonertinib with a mixed inhibitory mechanism. In pharmacokinetic experiments of rats, it was observed that nicardipine could significantly alter the pharmacokinetic profiles of almonertinib, including AUC_(0-∞), AUC_(0-t) and C_max, but had no effect on the metabolism of HAS-719.

Conclusion: According to the findings, it was indicated that nicardipine could inhibit the metabolism of almonertinib in vitro and in vivo.

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优化同时定量阿莫替尼和 HAS-719 的灵敏可靠的 UPLC-MS/MS 方法，并将其应用于研究与尼卡地平的相互作用。

背景阿莫替尼主要通过CYP3A4代谢，因此可能与多种通过CYP3A4代谢的药物发生相互作用，导致全身暴露量的变化：本实验优化并全面验证了一种准确、简便的超高效液相色谱串联质谱（UPLC-MS/MS）检测方法，用于同时定量检测阿莫替尼及其代谢物HAS-719，并研究了阿莫替尼与尼卡地平在体内和体外的药物相互作用（DDI）：采用UPLC-MS/MS和多反应监测（MRM）正离子模式检测分析物，阿莫替尼的离子跃迁为m/z 526.01 → 72.04，HAS-719的离子跃迁为m/z 512.18 → 455.08，IS的离子跃迁为m/z 447.16 → 128.11：阿仑替尼和HAS-719在0.5-200 ng/mL的校准范围和0.5-100 ng/mL的校准范围内线性良好。两种分析物的定量下限（LLOQ）均为 0.5 纳克/毫升。方法学验证所要求的精密度、准确度、稳定性、基质效应和提取回收率均符合FDA指南的要求。随后，UPLC-MS/MS测定法成功用于阿莫替尼和尼卡地平在体内和体外的相互作用。在大鼠肝脏微粒体（RLM）中，尼卡地平对阿莫替尼代谢的半最大抑制浓度（IC50）为1.19 μM，尼卡地平对阿莫替尼代谢的抑制机制为混合抑制。在大鼠药代动力学实验中观察到，尼卡地平能显著改变阿莫替尼的药代动力学特征，包括AUC（0-∞）、AUC（0-t）和Cmax，但对HAS-719的代谢没有影响：结论：研究结果表明，尼卡地平能抑制阿莫替尼的体内外代谢。

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来源期刊

Pharmaceutical Biology 医学-药学

CiteScore

6.70

自引率

2.60%

发文量

191

审稿时长

1 months

期刊介绍： Pharmaceutical Biology will publish manuscripts describing the discovery, methods for discovery, description, analysis characterization, and production/isolation (including sources and surveys) of biologically-active chemicals or other substances, drugs, pharmaceutical products, or preparations utilized in systems of traditional medicine. Topics may generally encompass any facet of natural product research related to pharmaceutical biology. Papers dealing with agents or topics related to natural product drugs are also appropriate (e.g., semi-synthetic derivatives). Manuscripts will be published as reviews, perspectives, regular research articles, and short communications. The primary criteria for acceptance and publication are scientific rigor and potential to advance the field.