Abdominal irradiation modulates 5-Fluorouracil pharmacokinetics

Abstract

BackgroundConcurrent chemoradiation with 5-fluorouracil (5-FU) is widely accepted for treatment of abdominal malignancy. Nonetheless, the interactions between radiation and 5-FU remain unclear. We evaluated the influence of abdominal irradiation on the pharmacokinetics of 5-FU in rats.MethodsThe radiation dose distributions of cholangiocarcinoma patients were determined for the low dose areas, which are generously deposited around the intrahepatic target volume. Then, corresponding single-fraction radiation was delivered to the whole abdomen of Sprague-Dawley rats from a linear accelerator after computerized tomography-based planning. 5-FU at 100 mg/kg was intravenously infused 24 hours after radiation. A high-performance liquid chromatography system equipped with a UV detector was used to measure 5-FU in the blood. Ultrafiltration was used to measure protein-unbound 5-FU.ResultsRadiation at 2 Gy, simulating the daily human treatment dose, reduced the area under the plasma concentration vs. time curve (AUC) of 5-FU by 31.7% compared to non-irradiated controls. This was accompanied by a reduction in mean residence time and incremental total plasma clearance values, and volume of distribution at steady state. Intriguingly, low dose radiation at 0.5 Gy, representing a dose deposited in the generous, off-target area in clinical practice, resulted in a similar pharmacokinetic profile, with a 21.4% reduction in the AUC. This effect was independent of protein binding capacity.ConclusionsAbdominal irradiation appears to significantly modulate the systemic pharmacokinetics of 5-FU at both the dose level for target treatment and off-target areas. This unexpected and unwanted influence is worthy of further investigation and might need to be considered in clinical practice.

Regulation of X-Ray Irradiation on the Activity and Expression Levels of CYP1A2 and CYP2E1 in Rats

“…Our results are reminiscent of the effect of irradiation on the pharmacokinetics of 5-fluorouracil and irinotecan hydrochloride reported in recent studies. Whole pelvic and abdominal g-ray irradiation with 2 Gy decreased the AUC of 5-fluorouracil in rats by 21.5% and 31.7%, respectively (Hsieh et al, 2010;Hsieh et al, 2011;Hsieh et al, 2015). Our previous study indicated that whole-body X-ray irradiation decreased the AUC of irinotecan hydrochloride and increased the CL .…”

Effect of X‐ray irradiation on pharmacokinetics of irinotecan hydrochloride and expression of CES1 and CYP3A1 in rats

“…Our results are similar with the effect of local irradiation on the pharmacokinetics of 5‐fluorouracil reported in recent studies. Whole pelvic and abdominal irradiation with 2 Gy reduced the AUC of 5‐fluorouracil in rats by 21.5 and 31.7%, respectively , and the local whole pelvic RT at 2 Gy reduced the AUC and MRT of 5‐fluorouracil by 21.5 and 31.5%, respectively . However, the whole pelvic irradiation increased the AUC of cisplatin in the plasma by 80% at 0.5 Gy and 87% at 2 Gy, respectively .…”

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

“…Each group's data were collected from six rats. Dosages of 0.5 and 2 Gy for the rats and 100 mg/kg as a feasible 5-FU dose in rats to examine the 5-FU pharmacokinetic parameters were determined from the results of previous reports (Hsieh et al, 2010;Hsieh et al, 2011;Hsieh et al, 2015). Twenty hours after RT, FIGURE 1 | (A) The irradiation field of the whole pelvis.…”

“…5-FU was administered via PE50 cannula into the femoral vein, and blood was collected through PE50 cannula from the jugular vein. the rats were administered 100 mg/kg of 5-FU in 2 ml of normal saline by intravenous infusion into the femoral vein over a 2-min period (Hsieh et al, 2010) ( Figure 1B). A 150-ml blood sample was withdrawn from the jugular vein with a fraction collector according to a programmed schedule at 5, 15, 30, 45, and 60 min and 1.5, 2, 2.5, and 3 h following drug administration.…”

“…In the past, RT has been used as a local treatment (Elsasser and Scholz, 2007). 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 area under the plasma concentration versus time curve (AUC) of 5-FU is reduced by RT (Hsieh et al, 2015), and the excretion of 5-FU is facilitated by RT (Hsieh et al, 2011).…”