Wang Jinhui, Chen Feifei, Jiang Hui, Xu Jia, Meng Deru, Geng Peiwu, Dai Dapeng, Hu Jingbo, Zhou Yunfang, Zhou Quan, Wang Shuanghu
Institute of Drug Discovery Technology, Ningbo University, Ningbo, China.
The Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People's Hospital of Lishui, Lishui, China.
Front Pharmacol. 2021 Jan 5;11:593518. doi: 10.3389/fphar.2020.593518. eCollection 2020.
Poziotinib is an orally active, irreversible, pan-HER tyrosine kinase inhibitor used to treat non-small cell lung cancer, breast cancer, and gastric cancer. Poziotinib is currently under clinical investigation, and understanding its drug-drug interactions is extremely important for its future development and clinical application. The cocktail method is most suitable for evaluating the activity of cytochrome P450 enzymes (CYPs). As poziotinib is partially metabolized by CYPs, cocktail probes are used to study the interaction between drugs metabolized by each CYP subtype. Midazolam, bupropion, dextromethorphan, tolbutamide, chlorzoxazone, phenacetin, and their metabolites were used to examine the effects of poziotinib on the activity of cyp1a2, 2b1, 2d1, 2c11, 2e1, and 3a1/2, respectively. The experiment was carried out by using rat liver microsomes (RLMs), whereas the experiment involved the comparison of the pharmacokinetic parameters of the probes after co-administration with poziotinib to rats to those of control rats treated with only probes. UPLC-MS/MS was used to detect the probes and their metabolites in rat plasma and rat liver microsomes. The results revealed that the half-maximal inhibitory concentration values of bupropion and tolbutamide in RLMs were 8.79 and 20.17 μM, respectively, indicating that poziotinib showed varying degrees of inhibition toward cyp2b1 and cyp2c11. Poziotinib was a competitive inhibitor of cyp2b1 and cyp2c11, with Ki values of 16.18 and 17.66 μM, respectively. No time- or concentration-dependence of inhibition by poziotinib was observed toward cyp2b1 and cyp2c11 in RLMs. Additionally, no obvious inhibitory effects were observed on the activity of cyp1a2, cyp2d1, cyp2e1, and cyp3a1/2. analysis revealed that bupropion, tolbutamide, phenacetin, and chlorzoxazone showed significantly different pharmacokinetic parameters after administration ( < 0.05); there was no significant difference in the pharmacokinetic parameters of dextromethorphan and midazolam. These results show that poziotinib inhibited cyp2b1 and cyp2c11, but induced cyp1a2 and cyp2e1 in rats. Thus, poziotinib inhibited cyp2b1 and cyp2c11 activity in rats, suggesting the possibility of interactions between poziotinib and these CYP substrates and the need for caution when combining them in clinical settings.
波齐替尼是一种口服活性、不可逆的泛HER酪氨酸激酶抑制剂，用于治疗非小细胞肺癌、乳腺癌和胃癌。波齐替尼目前正在进行临床研究，了解其药物相互作用对其未来的开发和临床应用极为重要。鸡尾酒法最适合评估细胞色素P450酶（CYPs）的活性。由于波齐替尼部分由CYPs代谢，因此使用鸡尾酒探针来研究每种CYP亚型代谢的药物之间的相互作用。分别使用咪达唑仑、安非他酮、右美沙芬、甲苯磺丁脲、氯唑沙宗、非那西丁及其代谢物来检测波齐替尼对cyp1a2、2b1、2d1、2c11、2e1和3a1/2活性的影响。实验采用大鼠肝微粒体（RLMs）进行，而实验则涉及将波齐替尼与探针共同给药给大鼠后，比较探针与仅用探针处理的对照大鼠的药代动力学参数。使用超高效液相色谱-串联质谱法（UPLC-MS/MS）检测大鼠血浆和大鼠肝微粒体中的探针及其代谢物。结果显示，RLMs中安非他酮和甲苯磺丁脲的半数最大抑制浓度值分别为8.79和20.17 μM，表明波齐替尼对cyp2b1和cyp2c11表现出不同程度的抑制作用。波齐替尼是cyp2b1和cyp2c11的竞争性抑制剂，Ki值分别为16.18和17.66 μM。在RLMs中未观察到波齐替尼对cyp2b1和cyp2c11的抑制作用存在时间或浓度依赖性。此外，未观察到对cyp1a2、cyp2d1、cyp2e1和cyp3a1/2活性有明显抑制作用。分析显示，给药后安非他酮、甲苯磺丁脲、非那西丁和氯唑沙宗的药代动力学参数有显著差异（<0.05）；右美沙芬和咪达唑仑的药代动力学参数无显著差异。这些结果表明，波齐替尼在大鼠中抑制cyp2b1和cyp2c11，但诱导cyp1a2和cyp2e1。因此，波齐替尼在大鼠中抑制cyp2b1和cyp2c11活性，提示波齐替尼与这些CYP底物之间可能存在相互作用，在临床联合使用时需要谨慎。
