帕纳替尼被批准用于对先前的酪氨酸激酶抑制剂（TKI）治疗耐药或不耐受的慢性粒细胞白血病（CML）患者。鉴于普纳替尼服用后可引起明显的心脏毒性，而大多数中药均具有心脏保护作用，临床上可以联合用药以减轻不良反应。采用超高效液相色谱串联质谱法（UPLC-MS/MS）优化并充分验证了普纳替尼及其代谢物N-去甲基普纳替尼的定量测定。并研究了普纳替尼与番茄红素和紫草素的体内和体外药物相互作用（DDI）。生物分析方法学结果表明，普纳替尼和N-去甲基普纳替尼在血浆样品中具有良好的线性，其选择性、准确度、精密度、稳定性、基质效应和回收率均满足样品定量分析的需要。动物实验中，与对照组相比，番茄红素和紫草素显着改变了ponatinib的药代动力学参数，包括AUC(0-t)、AUC(0-∞)和CLz/F，而对N的药代动力学参数没有影响。 -去甲基帕纳替尼。体外相互作用研究表明，番茄红素对大鼠肝微粒体（RLM）和人肝微粒体（HLM）中的普纳替尼代谢表现出混合抑制机制。并且，紫草素分别在 RLM 中表现出混合抑制机制，在 HLM 中表现出竞争性抑制机制。综上所述，UPLC-MS/MS方法可以准确、灵敏地定量ponatinib和N-desmethyl ponatinib，为ponatinib与番茄红素或紫草素的临床联合用药提供进一步的参考。版权所有©2024 Elsevier B.V.保留所有权利。

Ponatinib is approved for use in patients with chronic myeloid leukemia (CML) who are resistant to or intolerant to prior tyrosine kinase inhibitor (TKI) therapy. Given that ponatinib can induce significant cardiotoxicity when taken, and that most Chinese medicines have cardioprotective effects, it is possible to administer them in combination in clinic to alleviate adverse effects. The quantitative determination of ponatinib and its metabolite N-desmethyl ponatinib was optimized and fully verified by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). And the drug-drug interactions (DDI) of ponatinib with lycopene and shikonin, both in vivo and in vitro, were studied. The results of bioanalytical methodology showed that ponatinib and N-desmethyl ponatinib had good linearity in plasma samples, and their selectivity, accuracy, precision, stability, matrix effect and recovery were all satisfied with the need of quantitative analysis of samples. In animal experiments, compared with the control group, lycopene and shikonin significantly changed the pharmacokinetic parameters of ponatinib, including AUC(0-t), AUC(0-∞) and CLz/F, while having no effect on the pharmacokinetic parameters of N-desmethyl ponatinib. In vitro interaction studies indicated that lycopene showed mixed inhibition mechanism on ponatinib metabolism in both rat liver microsomes (RLM) and human liver microsomes (HLM). And, shikonin displayed mixed inhibition mechanism in RLM and competitive inhibition mechanism in HLM, respectively. In summary, the UPLC-MS/MS method can accurately and sensitively quantify ponatinib and N-desmethyl ponatinib, and provide further reference for clinical drug combination between ponatinib and lycopene or shikonin.Copyright © 2024 Elsevier B.V. All rights reserved.