A predictive biomarker for altered 5‐fluorouracil pharmacokinetics following repeated administration in a rat model of colorectal cancer

Abstract

The relationship between the plasma ratio of dihydrouracil/uracil (UH2/Ura) and hepatic dihydropyrimidine dehydrogenase (DPD) activity after repeated 5-fluorouracil (5-FU) treatment in rats with colorectal cancer (CRC) was investigated. Repeated intravenous 5-FU bolus injections resulted in a significant decrease in the total clearance (CLtot ) and an increased area under the curve (AUC0-∞ ) in CRC rats. Furthermore, the hepatic DPD levels and the plasma ratio of UH2/Ura decreased significantly and lost their circadian rhythms in CRC rats treated repeatedly with 5-FU, although significant circadian variation in the two parameters was observed in the control CRC rats. Moreover, a significant correlation was found between the plasma ratio of UH2/Ura and hepatic DPD activity in CRC rats untreated and treated with single or repeated 5-FU administration (r(2) = 0.865, p < 0.01). The ratio of UH2/Ura in plasma could be a predictive biomarker of the suppression of hepatic DPD levels during repeated 5-FU-based treatment. Furthermore, by plotting the observed pharmacokinetic parameters of 5-FU against hepatic DPD activity levels predicted by the ratio of UH2/Ura in plasma, AUC0-∞ , CLtot and half-life (t1/2 ) were closely linked to predicted hepatic DPD activity levels. These observations suggest that the factor that significantly influences the AUC0-∞ , CLtot and t1/2 of 5-FU after single or repeated administration of 5-FU is the hepatic DPD activity and it could be assessed by the ratio of UH2/Ura in plasma.

Association between the pharmacokinetics of capecitabine and the plasma dihydrouracil to uracil ratio in rat: A surrogate biomarker for dihydropyrimidine dehydrogenase activity

“…For instance, Tateishi et al () reported that the DPD activity and protein levels in rat models of hepatic failure were higher than those in their controls, although the mechanisms were not clear. In 1,2‐dimethylhydrazine‐induced CRC model rats, the hepatic DPD activity and the plasma UH 2 /Ura ratio were higher than those in the control rats (Kobuchi, Ito, et al, ; Kobuchi, Kuwano, et al, ). Moreover, the DPD activity in human carcinoma cells was higher than that in normal cells (Miyazaki et al, ).…”

“…The present study results suggest that the possible increase in the DPD activity with the administration of capecitabine also affects the changes in the Ura and UH 2 plasma levels. Alternatively, repetitive exposure of 5‐FU can suppress the DPD activity, and this can be assessed by the plasma UH 2 /Ura ratio (Kobuchi, Ito, et al, ; Kobuchi, Kuwano, et al, ). In clinical studies on capecitabine, an increase of 5‐FU exposure after multiple administration of capecitabine has been reported, whereas there was no difference in the pharmacokinetics and no clinically significant accumulation of capecitabine and its metabolites (Hyodo et al, ; Saeki et al, ).…”

“…Alternatively, repetitive exposure of 5-FU can suppress the DPD activity, and this can be assessed by the plasma UH 2 /Ura ratio Kobuchi, Kuwano, et al, 2013). In clinical studies on capecitabine, an increase of 5-FU exposure after multiple administration of capecitabine has been reported, whereas there was no difference in the pharmacokinetics and no clinically significant accumulation of capecitabine and its metabolites (Hyodo et al, 2006;Saeki et al, 2005).…”

“…After centrifugation of the blood samples at 14,000 × g for 15 min, the plasma samples were stored at −80 °C until analysis. Plasma concentrations of capecitabine, 5′‐DFCR, 5′‐DFUR, 5‐FU, Ura and UH 2 were determined by LC–MS/MS method, which was conducted and reported in our previous report (Kobuchi, Ito, Okada, Imoto, & Takada, ; Kobuchi et al, ; Kobuchi et al, ).…”

Association between circadian and chemotherapeutic cycle effects on plasma concentration of 5‑fluorouracil and the clinical outcome following definitive 5‑fluorouracil/cisplatin‑based chemoradiotherapy in patients with esophageal squamous cell carcinoma

“…Of note, Cyc significantly correlated with pretherapeutic leucocyte counts: Lower leucocyte counts had greater effects on the magnitude of plasma 5-FU level elevation in the second cycle. Higher 5-FU concentrations in the plasma after repeated treatment with 5-FU in animals and patients have been reported (4,5,13,14). This 5-FU elevation is related to a decrease in clearance and hepatic dihydropyrimidine dehydrogenase (DPD) activity levels (13,14).…”