Metabolite characterisation of the peptide-drug conjugate LN005 in liver S9s by UHPLC-Orbitrap-HRMS.

IF 1.3 4区医学 Q4 PHARMACOLOGY & PHARMACY

Xenobiotica Pub Date : 2024-01-01 Epub Date: 2024-01-08 DOI:10.1080/00498254.2023.2289635

Yali Yuan, Weiqiang Wang, Jing Luo, Chongzhuang Tang, Yuandong Zheng, Jinghua Yu, Honghong Xu, Mingshe Zhu, Taijun Hang, Hao Wang, Xingxing Diao

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引用次数: 0

Abstract

LN005 is a peptide-drug conjugate (PDC) targeting glucose-regulated protein 78 (GRP78) to treat several types of cancer, such as breast, colon, and prostate cancer.As a new drug modality, understanding its metabolism and elimination pathways will help us to have a whole picture of it. Currently, there are no metabolic studies on LN005; therefore, this study aimed to investigate the metabolism of LN005, clarify its metabolic profile in the liver S9s of different species, and identify the major metabolic pathways and differences between species.The incubation samples were measured by ultra-high performance liquid chromatography combined with orbitrap tandem mass spectrometry (UHPLC-Orbitrap-HRMS).The results showed that LN005 was metabolised by liver S9s, and four metabolites were identified. The main metabolic pathway of LN005 in liver S9s was oxidative deamination to ketone or hydrolysis. Similar metabolic profiles were observed in mouse, rat, dog, monkey, and human liver S9s, indicating no differences between these four animal species and humans.This study provides information for the structural modification and optimisation of LN005 and affords a reference for subsequent animal experiments and human metabolism of other PDCs.

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肽-药物偶联物LN005在肝脏S9s代谢产物的UHPLC-Orbitrap-HRMS表征。

1. LN005是一种靶向葡萄糖调节蛋白78 (GRP78)的肽-药物偶联物(PDC)，用于治疗多种类型的癌症，如乳腺癌、结肠癌和前列腺癌。作为一种新的药物形态，了解其代谢和消除途径将有助于我们对其有一个全面的了解。目前还没有关于LN005的代谢研究;因此，本研究旨在研究LN005的代谢情况，明确其在不同物种肝脏s9中的代谢特征，并确定其主要代谢途径及物种间差异。3 .采用超高效液相色谱-轨道阱串联质谱法(UHPLC-Orbitrap-HRMS)对培养样品进行测定。结果表明，LN005被肝脏S9s代谢，鉴定出4种代谢物。LN005在肝脏S9s中的主要代谢途径为氧化脱胺生成酮或水解。在小鼠、大鼠、狗、猴和人的肝脏S9s中观察到相似的代谢谱，表明这四种动物与人类之间没有差异。本研究为LN005的结构修饰和优化提供了信息，也为后续的动物实验和其他PDCs的人体代谢提供了参考。

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

Xenobiotica 医学-毒理学

CiteScore

3.80

自引率

5.60%

发文量

审稿时长

2 months

期刊介绍： Xenobiotica covers seven main areas, including:General Xenobiochemistry, including in vitro studies concerned with the metabolism, disposition and excretion of drugs, and other xenobiotics, as well as the structure, function and regulation of associated enzymesClinical Pharmacokinetics and Metabolism, covering the pharmacokinetics and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in manAnimal Pharmacokinetics and Metabolism, covering the pharmacokinetics, and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in animalsPharmacogenetics, defined as the identification and functional characterisation of polymorphic genes that encode xenobiotic metabolising enzymes and transporters that may result in altered enzymatic, cellular and clinical responses to xenobioticsMolecular Toxicology, concerning the mechanisms of toxicity and the study of toxicology of xenobiotics at the molecular levelXenobiotic Transporters, concerned with all aspects of the carrier proteins involved in the movement of xenobiotics into and out of cells, and their impact on pharmacokinetic behaviour in animals and manTopics in Xenobiochemistry, in the form of reviews and commentaries are primarily intended to be a critical analysis of the issue, wherein the author offers opinions on the relevance of data or of a particular experimental approach or methodology