Development of UPLC–MS/MS method for studying the pharmacokinetic interactions of fuzuloparib with curcumin in rats

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 a...

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Published in:Journal of pharmaceutical and biomedical analysis 2024-10, Vol.249, p.116383, Article 116383
Main Authors: Wu, Hualu, Xie, Saili, Chen, Xiaohai, Xia, Hailun, Shen, Yuxin, Xu, Ren-ai, Tan, Wei, Zhan, Ruanjuan
Format: Article
Language:English
Subjects:
Curcumin
Drug-drug interaction
Fuzuloparib
Inhibition mechanism
UPLC-MS/MS
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Summary: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. •An UPLC-MS/MS assay for the determination of fuzuloparib and its metabolite SHR165202 was developed and used to study DDIs.•Inhibitory effect of curcumin on fuzuloparib was found.•Verified the inhibitory mechanism of curcumin on fuzuloparib.
ISSN:0731-7085
1873-264X
1873-264X
DOI:10.1016/j.jpba.2024.116383