Liu Ju-Han, Tsai Tung-Hu, Chen Yu-Jen, Wang Li-Ying, Liu Hsin-Yu, Hsieh Chen-Hsi
School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan.
Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan.
Front Pharmacol. 2020 Feb 27;11:141. doi: 10.3389/fphar.2020.00141. eCollection 2020.
The effects of radiotherapy (RT) on the pharmacokinetics (PK) of 5-FU and 5-fluoro-5,6-dihydro-uracil (5-FDHU) were investigated by animal experiments.
Whole-pelvis RT with 0.5 and 2 Gy was delivered to Sprague-Dawley rats. 5-FU at 100 mg/kg was intravenously infused 24 h after radiation. The pharmacokinetics of 5-FU and 5-FDHU in the plasma and bile system were calculated.
The areas under the concentration versus time curve (AUC) of 5-FU in the plasma were reduced by local irradiation by 23.7% at 0.5 Gy (P < 0.001) and 35.3% at 2 Gy (P < 0.001). The AUCs of 5-FDHU were also reduced by 21.4% at 0.5 Gy (P < 0.001) and 51.5% at 2 Gy (P < 0.001). Irradiation significantly increased the clearance values (CLs) of 5-FU by 30.6% at 0.5 Gy and 50.1% at 2 Gy, respectively. The CLs of 5-FDHU were increased by 27.2% at 0.5 Gy and 106% at 2 Gy. The AUCs of 5-FU in the bile were increased by 36.7% at 0.5 Gy (P < 0.001) and 68.6% at 2 Gy (P = 0.005). The AUCs of 5-FDHU in the bile were increased by 40.3% at 0.5 Gy (P < 0.001) and 248.1% at 2 Gy (P < 0.001). The CLs of 5-FU in the bile were increased by 31.8% at 0.5 Gy and 11.2% at 2 Gy. However, the CLs of 5-FDHU in the bile were decreased by 29.1% at 0.5 Gy and 71.0% at 2 Gy.
Both conventional and low-dose irradiation can affect the pharmacokinetics of 5-FU and its metabolite, 5-FDHU. RT plus 5-FU could cause more adverse events than 5-FU alone by increasing the AUC ratio of 5-FU/5-FDHU. Irradiation decreases the AUC of 5-FU in the plasma, which may cause poor clinical outcomes.
通过动物实验研究了放疗（RT）对5-氟尿嘧啶（5-FU）和5-氟-5,6-二氢尿嘧啶（5-FDHU）药代动力学（PK）的影响。
对Sprague-Dawley大鼠进行0.5 Gy和2 Gy的全盆腔放疗。放疗后24小时静脉输注100 mg/kg的5-FU。计算血浆和胆汁系统中5-FU和5-FDHU的药代动力学。
局部照射后，血浆中5-FU的浓度-时间曲线下面积（AUC）在0.5 Gy时降低了23.7%（P<0.001），在2 Gy时降低了35.3%（P<0.001）。5-FDHU的AUC在0.5 Gy时也降低了21.4%（P<0.001），在2 Gy时降低了51.5%（P<0.001）。照射分别使0.5 Gy时5-FU的清除率（CL）显著增加30.6%，2 Gy时增加50.1%。0.5 Gy时5-FDHU的CL增加27.2%，2 Gy时增加106%。胆汁中5-FU的AUC在0.5 Gy时增加36.7%（P<0.001），在2 Gy时增加68.6%（P=0.005）。胆汁中5-FDHU的AUC在0.5 Gy时增加40.3%（P<0.001），在2 Gy时增加248.1%（P<0.001）。胆汁中5-FU的CL在0.5 Gy时增加31.8%，在2 Gy时增加11.2%。然而，胆汁中5-FDHU的CL在0.5 Gy时降低29.1%，在2 Gy时降低71.0%。
常规照射和低剂量照射均可影响5-FU及其代谢产物5-FDHU的药代动力学。放疗联合5-FU可能比单纯使用5-FU导致更多不良事件，因为增加了5-FU/5-FDHU的AUC比值。照射降低了血浆中5-FU的AUC，这可能导致不良的临床结局。
