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Update on metabolism of abemaciclib: In silico, in vitro, and in vivo metabolite identification and characterization using high resolution mass spectrometry.
Drug Testing and Analysis ( IF 2.6 ) Pub Date : 2020-01-14 , DOI: 10.1002/dta.2725 Disha Thakkar 1 , Abhijeet S Kate 1
Drug Testing and Analysis ( IF 2.6 ) Pub Date : 2020-01-14 , DOI: 10.1002/dta.2725 Disha Thakkar 1 , Abhijeet S Kate 1
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Abemaciclib was approved by the US Food and Drug Administration in 2015 as an advanced treatment for metastatic breast cancer. Identification and characterization of limited numbers of abemaciclib metabolites have been reported in the literature. Therefore, the current study focused on the investigation of the in vitro and in vivo metabolic fate of abemaciclib using high resolution mass spectrometry. Initially, a vulnerable site of metabolism was predicted by the Xenosite web predictor tool. Later, in vitro metabolites were identified from pooled rat liver microsomes, rat S9 fractions, and human liver microsomes. Finally, in vivo metabolites have been detected in plasma, urine, and feces matrix of male Sprague–Dawley rats. A total of 12 putative metabolites (11 phase I and 1 phase II) of abemaciclib and their metabolic pathways were proposed by considering accurate mass, mass fragmentation pattern, nitrogen rule, and ring double bonds of the detected metabolites. Abemaciclib was metabolized via hydroxylation, N‐oxidation, N‐dealkylation, oxidative deamination followed by reduction and sulfate conjugation. In the human liver microsomes, maximum numbers of metabolites (11 metabolites) were observed, from which M7, M8, M9, and M11 were human specific.
中文翻译：
abemaciclib的代谢更新：使用高分辨率质谱在计算机，体外和体内代谢物鉴定和表征。
Abemaciclib于2015年获得美国食品和药物管理局的批准，可作为转移性乳腺癌的先进治疗方法。文献中已经报道了有限数量的abemaciclib代谢物的鉴定和表征。因此，当前的研究集中在使用高分辨率质谱法研究abeciclib的体外和体内代谢命运。最初，Xenosite Web预测工具预测了一个易受代谢的部位。后来，从合并的大鼠肝微粒体，大鼠S9馏分和人肝微粒体中鉴定了体外代谢物。最后，体内在雄性Sprague–Dawley大鼠的血浆，尿液和粪便基质中检测到了代谢物。通过考虑准确的质量，质量碎裂模式，氮规则和检测到的代谢物的环双键，提出了abemaciclib的总共12种推定的代谢物（11种I期和1种II期）及其代谢途径。Abemaciclib通过羟基化，N-氧化，N-脱烷基，氧化脱氨，还原和硫酸盐结合而代谢。在人肝微粒体中，观察到最大数量的代谢物（11种代谢物），其中M7，M8，M9和M11是人类特异性的。
更新日期：2020-01-14
中文翻译：
abemaciclib的代谢更新：使用高分辨率质谱在计算机，体外和体内代谢物鉴定和表征。
Abemaciclib于2015年获得美国食品和药物管理局的批准，可作为转移性乳腺癌的先进治疗方法。文献中已经报道了有限数量的abemaciclib代谢物的鉴定和表征。因此，当前的研究集中在使用高分辨率质谱法研究abeciclib的体外和体内代谢命运。最初，Xenosite Web预测工具预测了一个易受代谢的部位。后来，从合并的大鼠肝微粒体，大鼠S9馏分和人肝微粒体中鉴定了体外代谢物。最后，体内在雄性Sprague–Dawley大鼠的血浆，尿液和粪便基质中检测到了代谢物。通过考虑准确的质量，质量碎裂模式，氮规则和检测到的代谢物的环双键，提出了abemaciclib的总共12种推定的代谢物（11种I期和1种II期）及其代谢途径。Abemaciclib通过羟基化，N-氧化，N-脱烷基，氧化脱氨，还原和硫酸盐结合而代谢。在人肝微粒体中，观察到最大数量的代谢物（11种代谢物），其中M7，M8，M9和M11是人类特异性的。
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