Local pelvic irradiation modulates Pharmacokinetics of 5-Fluorouracil in the plasma but not in the Lymphatic System.

Chen-Hsi Hsieh,Mei-Ling Hou,Li-Ying Wang,Yu-Jen Chen,Tung-Hu Tsai,Hung-Chi Tai

doi:10.1186/s12885-015-1344-4

Abstract

Background5-fluorouracil (5-FU) is employed to enhance radiotherapy (RT) effect. Here, we evaluated the influence of whole-pelvic irradiation on the pharmacokinetics (PK) of 5-FU in plasma and lymphatic system of rats as the experimental model.MethodsRT with 2 Gy was delivered to the whole pelvis of Sprague–Dawley rats. 5-FU at 100 mg/kg was intravenously infused 24 hours after radiation. The pharmacokinetics of 5-FU in plasma and lymphatic system were calculated.ResultsRT at 2 Gy reduced the area under the plasma concentration vs. time curve and mean residence time of 5-FU by 21.5% and 31.5%, respectively compared with those of non-RT controls. By contrast, RT at 2 Gy increased drug clearances of 5-FU by 28.2% when compared with those of non-RT controls. There was no significant difference in T1/2, Cmax and Vss in plasma between both groups. Intriguingly, 5-Fu could be detected in the lymphatic system. In addition, the AUC in 5-FU without and with RT was 3.3-fold and 4.9-fold greater for lymph than for plasma, respectively. Compared with the non-RT group, the RT group showed increase in distribution of 5-FU in the lymphatic system (p = 0.001).ConclusionsThe local whole pelvic RT at 2 Gy could modulate systemic PK of 5-FU in plasma of rats and intravenous 5-FU passing into the lymphatic system was proved. The metabolism of 5-FU might be modulated by RT but the distribution of 5-FU from blood circulation to the lymphatic system might not be changed. The RT-PK phenomena in plasma provide references for adjustment of drug administration. Chemotherapy drugs entering the lymphatic system is worthy of further investigation.

Highlights

Five-fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents of concurrent chemoradiation therapy (CCRT) for enhancing radiation therapy (RT) effects [1,2,3,4]
For T3, T4 or node-positive rectal cancer patients, adjuvant CCRT improves the locoregional failure control and overall survival by 10-15% when compared with surgery or adjuvant
Our recent studies reported that local RT could modulate the systemic pharmacokinetics (PK) of 5-FU with different RT doses in an experimental rat model [13,14] through matrix metalloproteinase-8 (MMP-8) [15]

Summary

Introduction

Five-fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents of concurrent chemoradiation therapy (CCRT) for enhancing radiation therapy (RT) effects [1,2,3,4]. Lymph node metastases are common among rectal cancer patients with incidence ranging between 5% and 35% even in T1 and T2 stages [5]. For T3, T4 or node-positive rectal cancer patients, adjuvant CCRT improves the locoregional failure control and overall survival by 10-15% when compared with surgery or adjuvant. Neoadjuvant CCRT followed by surgery improves locoregional control for rectal cancer patients [9]. CCRT reduces the risks of local recurrences and regional lymph node metastases. Our recent studies reported that local RT could modulate the systemic pharmacokinetics (PK) of 5-FU with different RT doses in an experimental rat model [13,14] through matrix metalloproteinase-8 (MMP-8) [15]

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Conclusion