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Bioanalysis of EGFRm inhibitor osimertinib, and its glutathione cycle- and desmethyl metabolites by liquid chromatography-tandem mass spectrometry.

EGFRm抑制剂奥希替尼及其谷胱甘肽循环-和去甲基代谢物的液相色谱-串联质谱生物分析。

  • 影响因子:3.15
  • DOI:10.1016/j.jpba.2019.112871
  • 作者列表:"Rood JJM","van Haren MJ","Beijnen JH","Sparidans RW
  • 发表时间:2020-01-05
Abstract

:Osimertinib is a "third-generation'' oral, irreversible, tyrosine kinase inhibitor. It is used in the treatment of non-small cellular lung carcinoma and spares wild-type EGFR. Due to its reactive nature, osimertinib is, in addition to oxidative routes, metabolized through GSH coupling and subsequent further metabolism of these conjugates. The extent of the non-oxidative metabolism of osimertinib is unknown, and methods to quantify this metabolic route have not been reported yet. To gain insight into this metabolic route, a sensitive bioanalytical assay was developed for osimertinib, the active desmethyl metabolite AZ5104, and the thio-metabolites osimertinibs glutathione, cysteinylglycine, and cysteine conjugates was developed. The ease of synthesis of these metabolites was a key-part in the development of this assay. This was done through simple one-step synthesis and subsequent LC-purification. The compounds were characterized by NMR and high-resolution mass spectrometry. Sample preparation was done by a simple protein crash with acetonitrile containing the stable isotopically labeled internal standards for osimertinib and the thio-metabolites, partial evaporation of solvents, and reconstitution in eluent, followed by UHPLC-MS/MS quantification. The assay was successfully validated in a 2-2000 nM calibration range for all compounds except the glutathione metabolite, where the LLOQ was set at 6 nM due to low accuracy at 2 nM. Limited stability was observed for osimertinib, AZ5104, and the glutathione metabolite. The clinical applicability of the assay was demonstrated in samples of patients treated with 80 mg osimertinib once daily, containing all investigated compounds at detectable and quantifiable levels.

摘要

: 奥希替尼是一种 “第三代” 口服、不可逆的酪氨酸激酶抑制剂。它用于治疗非小细胞肺癌,并保留野生型EGFR。由于其反应性,奥希替尼除了氧化途径之外,还通过GSH偶联和随后这些缀合物的进一步代谢进行代谢。奥希替尼的非氧化代谢的程度是未知的,并且定量该代谢途径的方法尚未报道。为了深入了解这一代谢途径,开发了对奥希替尼、活性去甲基代谢物AZ5104 和硫代代谢物奥希替尼谷胱甘肽、半胱氨酰甘氨酸和半胱氨酸缀合物的灵敏生物分析测定法。合成这些代谢物的容易性是该测定开发的关键部分。这通过简单的一步合成和随后的LC纯化来完成。通过NMR和高分辨质谱对化合物进行了表征。样品制备是通过简单的蛋白质碰撞,含有奥希替尼稳定的同位素标记内标物和硫代代谢物的乙腈,部分蒸发溶剂,并在洗脱液中重构,随后进行uhplc-ms/MS定量。对于除谷胱甘肽代谢物之外的所有化合物,该测定在 2-2000 nm校准范围内成功验证,其中由于在 2 nm处的低准确度,LLOQ设定在 6 nm。观察到奥希替尼、AZ5104 和谷胱甘肽代谢物的稳定性有限。在每天一次 80 mg奥希替尼治疗的患者样品中证明了该测定法的临床适用性,其中包含所有可检测和可定量水平的研究化合物。

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影响因子:6.93
发表时间:2020-01-15
DOI:10.1002/ijc.32532
作者列表:["Hata A","Nakajima T","Matsusaka K","Fukuyo M","Morimoto J","Yamamoto T","Sakairi Y","Rahmutulla B","Ota S","Wada H","Suzuki H","Matsubara H","Yoshino I","Kaneda A"]

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翻译标题与摘要 下载文献
影响因子:6.93
发表时间:2020-01-01
DOI:10.1002/ijc.32530
作者列表:["Zhang L","Yang Y","Chai L","Bu H","Yang Y","Huang H","Ran J","Zhu Y","Li L","Chen F","Li W"]

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肺肿瘤,又叫支气管肺癌,是常见的恶性肿瘤之一。肺肿瘤的治疗为包括手术、中药、放疗、化疗及免疫等多学科的综合治疗。

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