Abdelhameed Ali S, Attwa Mohamed W, Al-Shaklia Nasser S, Kadi Adnan A
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
Students' University Hospital, Mansoura University, Mansoura 35516, Egypt.
R Soc Open Sci. 2019 Jun 5;6(6):190434. doi: 10.1098/rsos.190434. eCollection 2019 Jun.
Spebrutinib (SBT) is a Bruton's tyrosine kinase inhibitor. SBT is currently in phase II and phase I clinical trials for the management of rheumatoid arthritis and chronic lymphocytic leukaemia, respectively. We developed and validated a liquid chromatography tandem mass spectrometry analytical method to quantify SBT and investigate its metabolic stability. SBT and the naquotinib as internal standard were isocratically eluted on a C18 column. The linearity of the developed method is 5-500 ng ml ( ≥ 0.9999) in the human liver microsomes (HLMs) matrix. Good sensitivity was approved by the very low limit of detection (0.39 ng ml). Inter- and intra-assay accuracy values of -1.41 to 12.44 and precision values of 0.71% to 4.78%, were obtained. SBT was found to have an half-life (82.52 min) and intrinsic clearance (8.4 µl min mg) as computed following its incubation with HLMs. The latter finding, hypothesize that SBT could be slowly excreted from the body unlike other related tyrosine kinase inhibitors. So, drug plasma level and kidney function should be monitored because of potential bioaccumulation. To the best of our knowledge, this is considered the first analytical method for SBT quantification using LC-MS/MS with application to metabolic stability evaluation.
司布替尼（SBT）是一种布鲁顿酪氨酸激酶抑制剂。目前，SBT分别处于类风湿性关节炎和慢性淋巴细胞白血病治疗的II期和I期临床试验阶段。我们开发并验证了一种液相色谱串联质谱分析方法，用于定量SBT并研究其代谢稳定性。SBT和作为内标的那喹替尼在C18柱上进行等度洗脱。所开发方法在人肝微粒体（HLM）基质中的线性范围为5 - 500 ng/ml（≥0.9999）。极低的检测限（0.39 ng/ml）证明了该方法具有良好的灵敏度。批间和批内准确度值在-1.41至12.44之间，精密度值在0.71%至-4.78%之间。SBT与HLM孵育后计算得出的半衰期为82.52分钟，内在清除率为8.4 μl·min/mg。后一项发现表明，与其他相关酪氨酸激酶抑制剂不同，SBT可能从体内缓慢排泄。因此，由于存在潜在的生物蓄积，应监测药物血浆水平和肾功能。据我们所知，这被认为是第一种使用LC-MS/MS定量SBT并应用于代谢稳定性评估的分析方法。
