Jiang Chenchen, Chen Siqi, Huang Min, Yi Xiaojiao, Ding Haiying, Zhu Junfeng, Fang Luo
School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 311403, China; Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China.
Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China; Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Wenzhou Medical University, Wenzhou 325035, China.
J Pharm Biomed Anal. 2025 Nov 15;265:117037. doi: 10.1016/j.jpba.2025.117037. Epub 2025 Jun 19.
Doxorubicin (DOX) is an effective chemotherapeutic agent, but its use is limited by dose-dependent cardiotoxicity. Palmatine (PAL) has shown potential in preventing doxorubicin-induced cardiotoxicity (DIC); however, the underlying mechanism remains unclear. Since DOX accumulation in cardiomyocytes is a key factor in the development of cardiotoxicity, this study aims to explore the pharmacokinetic mechanisms through which PAL alleviates DIC. First, the effect of PAL on DIC was assessed based on H9c2 cardiomyocytes model using sulforhodamine B (SRB), lactate dehydrogenase (LDH), flow cytometry and Western blot assays, which demonstrated that PAL significantly attenuated DOX-induced cardiac toxicity and apoptosis. Second, a sensitive and efficient LC-MS/MS method was established to quantify DOX in H9c2 cells, with a lower limit of quantification of 10 nM and a total run time of 4 min per sample. Cellular pharmacokinetic study revealed that PAL significantly reduced DOX concentration in H9c2 cells. Finally, molecular docking analysis revealed that PAL exhibited low binding energies and formed hydrogen with uptake transporter proteins involved in DOX transport in cardiomyocytes, including organic cardi transporter (OCT) 1, OCT3, organic cation/carnitine transporter (OCTN) 1, OCTN2, and plasma membrane monoamine transporter (PMAT). This suggests a stable interaction between PAL and these transporters. In conclusion, PAL alleviates DIC, most likely by reducing myocardial DOX accumulation through the inhibition of uptake transporters. This study provides novel pharmacokinetic insights into the mechanism by which PAL mitigates DIC and underscores its potential as a complementary therapeutic agent in combination with DOX in clinical applications.
阿霉素（DOX）是一种有效的化疗药物，但其使用受到剂量依赖性心脏毒性的限制。巴马汀（PAL）已显示出预防阿霉素诱导的心脏毒性（DIC）的潜力；然而，其潜在机制仍不清楚。由于阿霉素在心肌细胞中的蓄积是心脏毒性发生的关键因素，本研究旨在探讨PAL减轻DIC的药代动力学机制。首先，基于H9c2心肌细胞模型，使用磺酰罗丹明B（SRB）、乳酸脱氢酶（LDH）、流式细胞术和蛋白质印迹分析评估了PAL对DIC的影响，结果表明PAL显著减轻了阿霉素诱导的心脏毒性和细胞凋亡。其次，建立了一种灵敏高效的LC-MS/MS方法来定量H9c2细胞中的阿霉素，定量下限为10 nM，每个样品的总运行时间为4分钟。细胞药代动力学研究表明，PAL显著降低了H9c2细胞中阿霉素的浓度。最后，分子对接分析显示，PAL表现出低结合能，并与参与心肌细胞中阿霉素转运的摄取转运蛋白形成氢键，这些转运蛋白包括有机阳离子转运体（OCT）1、OCT3、有机阳离子/肉碱转运体（OCTN）1、OCTN2和质膜单胺转运体（PMAT）。这表明PAL与这些转运蛋白之间存在稳定的相互作用。总之，PAL减轻DIC，很可能是通过抑制摄取转运蛋白来减少心肌阿霉素的蓄积。本研究为PAL减轻DIC的机制提供了新的药代动力学见解，并强调了其在临床应用中作为与阿霉素联合使用的辅助治疗剂的潜力。
