Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Students' University Hospital, Mansoura University, Mansoura 35516, Egypt.
Drug Des Devel Ther. 2020 Feb 25;14:783-793. doi: 10.2147/DDDT.S239458. eCollection 2020.
Talazoparib (BMN673) is a new poly(ADP-ribose) polymerase inhibitor that has been FDA approved for patients suffering from metastatic breast cancer with germline BRCA mutations.
In the current study, an accurate and efficient liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical methodology was developed for TZB estimation in addition to its metabolic stability assessment. TZB and lapatinib (LAP) (which is chosen as an internal standard; IS) were separated using reversed phase elution system (Hypersil C column) with an isocratic mobile phase. The linearity range of the established method was 5-500 ng/mL (r ≥ 0.999) in the human liver microsomes (HLMs) matrix. Different parameters were calculated to confirm the method sensitivity (limit of quantification was 2.0 ng/mL), and reproducibility (intra- and inter-day precision and accuracy were below 3.1%) of our methodology. For evaluation of TZB metabolic stability in HLM matrix, intrinsic clearance (9.59 µL/min/mg) and in vitro half-life (72.7 mins) were calculated. TZB treatment discontinuations were reported due to adverse events and dose accumulation, so in silico metabolic vulnerability (experimental and in silico) and toxicity assessment (in silico) of TZB were performed utilizing P450 Metabolism and DEREK modules of StarDrop software.
TZB is slowly metabolized by the liver. TZB was reported to be minimally metabolized by the liver that approved our outcomes. We do recommend that plasma levels be monitored in cases when talazoparib is used for a long period of time, since it is possible for TZB to bioaccumulate after multiple doses to toxic levels. According to our knowledge, the current method is considered the first LC-MS/MS methodology for evaluating TZB metabolic stability. Further drug discovery studies can be done depending on this concept allowing the designing of new series of compounds with more safety profile through reducing side effects and improving metabolic behavior.
Talazoparib（BMN673）是一种新型聚（ADP-核糖）聚合酶抑制剂，已获得美国食品和药物管理局批准，用于治疗携带生殖系 BRCA 突变的转移性乳腺癌患者。
在本研究中，建立了一种准确、高效的液相色谱-串联质谱（LC-MS/MS）分析方法，用于 TZB 的定量分析，并评估其代谢稳定性。TZB 和拉帕替尼（LAP）（选为内标；IS）采用反相洗脱系统（Hypersil C 柱），以等度洗脱方式分离。在人肝微粒体（HLM）基质中，建立方法的线性范围为 5-500ng/mL（r≥0.999）。计算了不同参数以确认方法的灵敏度（定量下限为 2.0ng/mL）和重现性（日内和日间精密度和准确度均低于 3.1%）。为评估 TZB 在 HLM 基质中的代谢稳定性，计算了内在清除率（9.59µL/min/mg）和体外半衰期（72.7 分钟）。由于不良反应和剂量蓄积，TZB 治疗被中断，因此利用 StarDrop 软件的 P450 代谢和 DEREK 模块进行了 TZB 的体外代谢脆弱性（实验和计算）和毒性评估（计算）。
TZB 主要在肝脏中缓慢代谢。TZB 主要在肝脏中代谢，这与我们的实验结果一致。我们建议在长时间使用他拉唑帕尼时监测血浆水平，因为多次给药后 TZB 可能会在体内蓄积至毒性水平。据我们所知，目前的方法被认为是评估 TZB 代谢稳定性的首个 LC-MS/MS 方法。根据这一概念，可以进行进一步的药物发现研究，设计出具有更高安全性的新化合物系列，通过减少副作用和改善代谢行为。
