利用UPLC-MS/MS揭示M-PEG6-OH的血浆动力学、氧化代谢和排泄行为

IF 3.1 3区医学 Q2 CHEMISTRY, ANALYTICAL

Journal of pharmaceutical and biomedical analysis Pub Date : 2025-07-25 DOI:10.1016/j.jpba.2025.117083

Yingxia Guo , Jiaxin Zhang , Runran Mei , Zihan Tang , Meichen Liu , Xixian Weng , Meiyun Shi , Lei Yin

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引用次数: 0

摘要

为了解决人们对聚乙二醇（PEG）为基础的形剂在体内行为的理解上的关键空白，本研究通过大鼠体内的综合药代动力学和代谢研究，系统地阐明了甲氧基聚乙二醇-羟基（M-PEG -OH）₆的生物学命运。采用经过验证的超高效液相色谱串联质谱（UPLC-MS/MS）方法，我们发现了独特的生物分布特征，包括快速的全身清除（半衰期(t1/2) = 1.92 ± 1.16 h）和广泛的组织渗透（表观分布体积(Vd) = 0.84 ± 0.45 L/kg），表明有效的血管外传播。排泄途径分析显示，主要是肾脏排泄，静脉注射后48 小时内，59.03 %的给药剂量在尿液中回收，与最小的粪便排泄（0.99 %）形成对比。定量代谢物谱分析确定M-PEG₅-CH₂COOH是通过末端羟基修饰的氧化转化产物。在同一时间段内，尿液中代谢产物（M-PEG5-CH2COOH）的相对丰度明显高于粪便，这为PEG聚合物的生物转化过程和代谢途径提供了重要的见解。这些发现首次建立了M-PEG-OH代谢轨迹和消除机制的系统证据，为优化具有增强生物相容性和可预测安全性的聚乙二醇化药物传递系统提供了重要参考。

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Unraveling the plasma dynamics, oxidative metabolism and excretion behavior of M-PEG6-OH by UPLC-MS/MS

Addressing critical gaps in understanding the in vivo behavior of polyethylene glycol (PEG)-based excipients, this study systematically elucidates the biological fate of methoxy-PEG₆-hydroxyl (M-PEG₆-OH) through comprehensive pharmacokinetic and metabolic investigations in rats. Employing a validated ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) methodology, we reveal distinctive biodistribution characteristics including rapid systemic clearance (Half-life (t_1/2) = 1.92 ± 1.16 h) and extensive tissue penetration (Apparent volume of distribution (V_d) = 0.84 ± 0.45 L/kg), suggesting efficient extravascular dissemination. Excretion pathways analysis demonstrated predominant renal elimination, with 59.03 % of the administered dose recovered in urine within 48 h post-IV injection, contrasting with minimal fecal excretion (0.99 %). Quantitative metabolite profiling identified M-PEG₅-CH₂COOH as the oxidative transformation product through terminal hydroxyl modification. The significantly higher relative abundance of metabolites (M-PEG₅-CH₂COOH) in urine compared to feces within the same time period provides critical insights into the biotransformation processes and metabolic pathways of the PEG polymer. These findings establish the first systematic evidence of metabolic trajectory and elimination mechanisms for M-PEG-OH, offering vital references for optimizing PEGylated drug delivery systems with enhanced biocompatibility and predictable safety profiles.

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来源期刊

Journal of pharmaceutical and biomedical analysis 医学-分析化学

CiteScore

6.70

自引率

5.90%

发文量

588

审稿时长

37 days

期刊介绍： This journal is an international medium directed towards the needs of academic, clinical, government and industrial analysis by publishing original research reports and critical reviews on pharmaceutical and biomedical analysis. It covers the interdisciplinary aspects of analysis in the pharmaceutical, biomedical and clinical sciences, including developments in analytical methodology, instrumentation, computation and interpretation. Submissions on novel applications focusing on drug purity and stability studies, pharmacokinetics, therapeutic monitoring, metabolic profiling; drug-related aspects of analytical biochemistry and forensic toxicology; quality assurance in the pharmaceutical industry are also welcome. Studies from areas of well established and poorly selective methods, such as UV-VIS spectrophotometry (including derivative and multi-wavelength measurements), basic electroanalytical (potentiometric, polarographic and voltammetric) methods, fluorimetry, flow-injection analysis, etc. are accepted for publication in exceptional cases only, if a unique and substantial advantage over presently known systems is demonstrated. The same applies to the assay of simple drug formulations by any kind of methods and the determination of drugs in biological samples based merely on spiked samples. Drug purity/stability studies should contain information on the structure elucidation of the impurities/degradants.