Fuzuloparib是一种新型的口服生物活性聚ADP核糖聚合酶抑制剂(PARPi),该药物于2020年获得中国监管机构(CRA)批准用于治疗铂类敏感性复发性卵巢,输卵管,和原发性腹膜癌。本研究首先提出了一种快速、准确的超高效液相色谱-串联质谱(UPLC-MS/MS)方法,用于分析夫草胺及其主要代谢产物(SHR165202)的含量,并在体外和体内研究中研究夫祖洛尼与姜黄素之间的药物相互作用。用乙腈沉淀蛋白质后,流动相由乙腈和0.1%甲酸组成,梯度洗脱用于成功分离夫祖洛帕尼,SHR165202和talazoparib(内标,IS).结果表明,在2-50ng/mL和1-20ng/mL的校准范围内,fuzuloparib和SHR165202具有良好的线性,分别。精度,准确度,稳定性,基体效应,方法验证所需的提取回收率均符合生物分析方法验证指南的要求。体外微粒体孵育实验,姜黄素对大鼠肝微粒体(RLM)和人肝微粒体(HLM)中的fuzuloparib均具有抑制作用,其半数最大抑制浓度(IC50)值为10.54μM和47.64μM,分别,相应的机制是非竞争性的。此外,通过分子对接验证了姜黄素对夫祖洛尼的抑制机制。在大鼠的药代动力学实验中,姜黄素显着改变了夫祖洛帕里布的血浆暴露,导致fuzuloparib的AUC(0-t)和Cmax显着增加,CLz/F显着降低。此外,代谢物SHR165202显示AUC(0-t)显着增加,AUC(0-∞),Tmax和Cmax以及CLz/F的显着降低。这进一步支持了姜黄素可以抑制夫祖洛帕尼的代谢的观点。因此,当在临床上共同施用夫祖洛帕尼和姜黄素时,建议监测夫祖洛帕尼的血浆水平,并密切关注不良反应。如有必要,需要减少夫祖洛帕尼的剂量。
Fuzuloparib is a novel orally bioactive poly-ADP-ribose polymerase inhibitor (PARPi), which was approved by the Chinese Regulatory Agency (CRA) in 2020 for the treatment of platinum-sensitive recurrent ovarian, fallopian tube, and primary peritoneal cancers. This study firstly presents a rapid and accurate ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for analyzing the levels of fuzuloparib and its major metabolite (SHR165202), and to investigate drug-drug interaction between fuzuloparib and curcumin in vitro and in vivo studies. After protein precipitation with acetonitrile, mobile phase consisted of acetonitrile and 0.1 % formic acid with a gradient elution was used to successfully separate fuzuloparib, SHR165202 and talazoparib (internal standard, IS). The results indicated that fuzuloparib and SHR165202 had good linearity over the calibration range of 2-50 ng/mL and 1-20 ng/mL, respectively. The precision, accuracy, stability, matrix effect, and extraction recovery required for methodological validation all complied with the requirements of the Bioanalytical Method Validation Guidelines. In vitro microsome incubation experiments, curcumin exhibited inhibitory effect on fuzuloparib in both rat liver microsomes (RLM) and human liver microsomes (HLM) with half-maximal inhibitory concentration (IC50) value of 10.54 μM and 47.64 μM, respectively, and the corresponding mechanism was non-competitive. Furthermore, the inhibitory mechanism of curcumin on fuzuloparib was validated through molecular docking. In pharmacokinetic experiments in rats, curcumin significantly altered the plasma exposure of fuzuloparib, resulting in significant increases in AUC(0-t) and Cmax of fuzuloparib and a significant decrease in CLz/F. Moreover, the metabolite SHR165202 showed significant increases in AUC(0-t), AUC(0-∞), Tmax and Cmax and a significant decrease in CLz/F. This further supports the notion that curcumin could inhibit the metabolism of fuzuloparib. Therefore, when co-administering fuzuloparib and curcumin in clinic, it is recommended to monitor plasma levels of fuzuloparib and pay close attention to adverse effects. If necessary, the dose of fuzuloparib needs to be reduced.