Head and neck irradiation modulates pharmacokinetics of 5-fluorouracil and cisplatin.
BACKGROUND
5-fluorouracil (5-FU) and cisplatin (CDDP) are used to enhance radiotherapy (RT) effect for head and neck (HN) cancers. However, the effect of local RT on systemic chemotherapeutics remains unclear. Here, we evaluated the influence of HN irradiation on the pharmacokinetics (PK) of 5-FU and CDDP in rats as experimental model.


METHODS
The radiation dose distributions of HN cancer patients were determined for the low dose areas, which are generously deposited around the target volume. Two Gy and 0.5 Gy RT were selected. Single-fraction radiation was delivered to the HN of Sprague-Dawley rats. 5-FU at 100 mg/kg or CDDP at 5 mg/kg was intravenously infused 24 hours after radiation.


RESULTS
Radiation at 2 Gy reduced the area under the plasma concentration vs. time curve (AUC) of 5-FU and CDDP by 16% and 29% compared to non-irradiated controls, respectively. This was accompanied by incremental total plasma clearance values. Intriguingly, low dose radiation at 0.5 Gy resulted in a similar pharmacokinetic profile, with a 17% and 33% reduction in the AUC of 5-FU and CDDP, respectively. The changes in AUC of bile, which increases with RT, were opposite to AUC of plasma for both drugs.


CONCLUSIONS
The local HN RT could modulate systemic PK of 5-FU and CDDP in rats. This unexpected RT-PK phenomena may provide a reference for adjustment of drug administration and is worthy of further investigation.


BACKGROUND
ClinicalTrials.gov ID NCT01755585 and NCT01609114.
Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, 155, Li-Nong Street Section 2, Taipei 112, Taiwan. thtsai@ym.edu.tw.
Chen-Hsi
CH
Hsieh
Mei-Ling
ML
Hou
Meng-Hsuan
MH
Chiang
Hung-Chi
HC
Tai
Hui-Ju
HJ
Tien
Li-Ying
LY
Wang
Tung-Hu
TH
Tsai
Yu-Jen
YJ
Chen
D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D002945:Cisplatin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005472:Fluorouracil / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006258:Head and Neck Neoplasms / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000532:radiotherapy*; D008297:Male; D011874:Radiometry; D051381:Rats; D017207:Rats, Sprague-Dawley; D014057:Tomography, X-Ray Computed
D002945:Cisplatin; D005472:Fluorouracil