Tsai Tung-Hu, Chen Yu-Jen, Wang Li-Ying, Hsieh Chen-Hsi
Institute of Traditional Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
Departments of Radiation Oncology, Mackay Memorial Hospital, Taipei 104, Taiwan.
Pharmaceutics. 2021 Mar 13;13(3):386. doi: 10.3390/pharmaceutics13030386.
This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT-PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC) by 74% ( = 0.001) in the RT group and by 69% ( = 0.001) in the RT group. The AUC was increased by 182.8% ( = 0.011) in the sequential RT group and by 213.2% ( = 0.016) in the sequential RT group. Both concurrent regimens, RT and RT, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib ) group. The concurrent regimens, both RT and RT, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).
本研究旨在评估传统放疗或高剂量放疗（RT）与瑞戈非尼药代动力学（PK）在同步或序贯方案中治疗肝细胞癌时的相互作用。设计了放疗与瑞戈非尼的同步和序贯体外及体内研究。在人肝癌Huh-7、HA22T和Hep G2细胞系中检测了放疗与瑞戈非尼在体外的相互作用。在自由活动的大鼠模型中证实了放疗条件下瑞戈非尼的放疗-药代动力学现象及生物分布。瑞戈非尼以剂量依赖方式抑制Huh-7细胞的活力。放疗后给予瑞戈非尼治疗可增强Huh-7细胞的凋亡。在同步方案中，放疗组的浓度-时间曲线下面积（AUC）降低了74%（ = 0.001），放疗组降低了69%（ = 0.001）。序贯放疗组的AUC增加了182.8%（ = 0.011），序贯放疗组增加了213.2%（ = 0.016）。与对照组（瑞戈非尼 ）相比，两种同步方案，即放疗和放疗，均明显降低了瑞戈非尼在心脏、肝脏、肺、脾脏和肾脏中的生物分布。与对照组相比，两种同步方案，即放疗和放疗，均显著降低了瑞戈非尼的生物分布。瑞戈非尼的药代动力学可通过非靶向照射和立体定向体部放疗（SBRT）进行调节。
