Local Irradiation Modulates the Pharmacokinetics of Metabolites in 5-Fluorouracil-Radiotherapy-Pharmacokinetics Phenomenon.

Ju-Han Liu,Tung-Hu Tsai,Chen-Hsi Hsieh,Yu-Jen Chen,Hsin-Yu Liu,Li-Ying Wang

doi:10.3389/fphar.2020.00141

Abstract

BackgroundThe 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.MethodsWhole-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.ResultsThe 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.ConclusionBoth 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.

Highlights

Five-fluorouracil (5-FU) a traditional chemotherapeutic agent used in concurrent chemoradiation therapy (CCRT) to enhance the radiotherapy (RT) effects in rectal cancer patients (Fisher et al, 1988)
Growing evidence shows that the systemic pharmacokinetics (PK) of anticancer drugs can be modulated by local RT with different RT doses; this is called the RT-PK phenomenon (Hsieh et al, 2010; Hsieh et al, 2013; Hsieh et al, 2015; Chen et al, 2017)
The absolute recoveries of 5-FU and 5-FDHU in bile ranged from 107.4% to 113.7% and 103.9% to 108.0%, respectively (Table 2)

Summary

Introduction

Five-fluorouracil (5-FU) a traditional chemotherapeutic agent used in concurrent chemoradiation therapy (CCRT) to enhance the radiotherapy (RT) effects in rectal cancer patients (Fisher et al, 1988). More than half of the catabolic activity of 5-FU in the liver through the dihydropyrimidine dehydrogenase (DPD) pathway generates toxic 5-fluoro-5,6-dihydro-uracil (5-FDHU), followed by fluoroureidopropionic acid and a-fluoro-b-alanine (Wasternack, 1980; Heggie et al, 1987; Bocci et al, 2000). The increased AUC ratio of 5-FU/5FDHU is associated with adverse events (Di Paolo et al, 2001), and the modulation of the catabolic pathway of 5-FU has an impact on the side effects and adverse reactions (Ezzeldin and Diasio, 2004). 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

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