Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education & Research, IDPL R&D Campus, Balanagar, Hyderabad, 500 037, India.
National Center for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500 607, India.
J Pharm Biomed Anal. 2018 Aug 5;157:59-74. doi: 10.1016/j.jpba.2018.05.008. Epub 2018 May 16.
Palbociclib (PAB) is a CDK4/6 inhibitor and U. S Food and Drug Administration (FDA) granted regular approval for the treatment of hormone receptor (HR) positive, metastatic breast cancer in combination with an aromatase inhibitor in postmenopausal women. Metabolite identification is a crucial aspect during drug discovery and development as the drug metabolites may be pharmacologically active or possess toxicological activity. As there are no reports on the metabolism studies of the PAB, the present study focused on investigation of the in vitro and in vivo metabolic fate of the drug. The in vitro metabolism studies were carried out by using microsomes (HLM and RLM) and S9 fractions (Human and rat). The in vivo metabolism of the drug was studied by administration of the PAB orally to the Sprague-Dawley rats followed by analysis of urine, faeces and plasma samples. The sample preparation includes simple protein precipitation (PP) followed by solid phase extraction (SPE). The extracted samples were analyzed by ultrahigh-performance liquid chromatography-quadruple time-of-flight tandem mass spectrometry (UHPLC/Q-TOF/MS/MS). A total of 14 metabolites were detected in in vivo matrices. The PAB was metabolized via hydroxylation, oxidation, sulphation, N-dealkylation, acetylation and carbonylation pathways. A few of the metabolites were also detected in in vitro samples. Metabolite identification and characterization were performed by using UHPLC/Q-TOF/MS/MS in combination with HRMS data. To identify the toxicity potential of these metabolites, in silico toxicity assessment was carried out using TOPKAT and DEREK softwares.
帕博西尼（PAB）是一种 CDK4/6 抑制剂，美国食品和药物管理局（FDA）批准其与芳香酶抑制剂联合用于治疗绝经后妇女的激素受体（HR）阳性、转移性乳腺癌。代谢产物鉴定是药物发现和开发过程中的一个关键方面，因为药物代谢产物可能具有药理学活性或具有毒理学活性。由于目前尚无关于 PAB 代谢研究的报道，本研究主要集中在研究该药物的体外和体内代谢命运。通过使用微粒体（HLM 和 RLM）和 S9 部分（人源和鼠源）进行体外代谢研究。通过给 Sprague-Dawley 大鼠口服给予 PAB 来研究药物的体内代谢，然后分析尿液、粪便和血浆样品。样品制备包括简单的蛋白沉淀（PP），然后进行固相萃取（SPE）。用超高效液相色谱-四极杆飞行时间串联质谱（UHPLC/Q-TOF/MS/MS）分析提取的样品。在体内基质中检测到 14 种代谢物。PAB 通过羟化、氧化、硫酸化、N-脱烷基化、乙酰化和羰基化途径代谢。一些代谢物也在体外样品中被检测到。通过使用 UHPLC/Q-TOF/MS/MS 结合 HRMS 数据进行代谢物鉴定和表征。为了评估这些代谢物的毒性潜力，使用 TOPKAT 和 DEREK 软件进行了计算机毒性评估。
