Pre-therapeutic Assessment of Plasma Dihydrouracil/Uracil Ratio for Predicting the Pharmacokinetic Parameters of 5-Fluorouracil and Tumor Growth in a Rat Model of Colorectal Cancer

Abstract

We investigated the correlation between plasma ratio of dihydrouracil/uracil (UH2/Ura), a possible surrogate biomarker of hepatic dihydropyrimidine dehydrogenase (DPD) activity, and 5-fluorouracil (5-FU) treatment efficacy in rats with colorectal cancer (CRC). 5-FU pharmacokinetic and pharmacodynamic studies were performed using DPD circadian variation in rats with 1,2-dimethylhydrazine-induced CRC. By plotting tumor volume after 5-FU treatment against pre-therapeutic plasma UH2/Ura, we inferred a linear relationship (r 2 =0.988). 5-FU concentration fluctuations induced by DPD activity variation affected tumor volume. In CRC patients receiving proper dosing regimens, plasma UH2/Ura could be an indirect biomarker for predicting 5-FU treatment efficacy, tumor growth, and 5-FU doses.Key words pharmacokinetics; biomarker; dihydropyrimidine dehydrogenase; anti-cancer agent Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality in Western and welldeveloped countries.1) Several environmental factors, including lifestyle, food, and body mass, play important roles in the induction and progression of CRC.2) Generally, surgery is the first-line treatment for patients with early-stage CRC (stage I or II), and it has been reported to afford a positive prognosis.3,4) However, surgery is less effective in patients with more advanced CRC (stage III); furthermore, patients with involvement of the lymph nodes are at a 50% risk of relapse following resection.3,4) Therefore, adjuvant chemotherapy is often prescribed for patients with lymph node involvement in order to reduce the risk of recurrence.5-Fluorouracil (5-FU), an analogue of the natural pyrimidine uracil (Ura), is an anti-cancer agent that is widely used in the management of patients with cancers of the gastrointestinal tract, breast, head, and neck.5-7) At present, 5-FU remains the single, most effective chemotherapeutic agent for the treatment of CRC. 8) Some studies have shown a relationship between systemic plasma levels of 5-FU and treatment efficacy. 9,10) Increased objective responses have been demonstrated when higher 5-FU area under the curve (AUC) values are maintained.9,10) However, the optimal method of using 5-FU remains debatable. Gamelin et al. conducted a randomized, phase III multicentre clinical trial involving 208 patients with metastatic CRC and reported wide pharmacokinetic (PK) variability and a large distribution of the optimal dose of 5-FU to achieve target 5-FU plasma levels.11) To achieve the prescribed target concentration levels, dose increase was required in 68% of the patients. The study investigators concluded that individual 5-FU dose adjustment on the basis of PK monitoring, not body surface area, is needed for an improved objective response rate, a higher survival rate, and fewer grade III/IV toxicities. In the field of oncology, researchers are focusing on the identification of predictive markers to improve the efficacy of 5-FU and decrease the likelihood of severe toxicity, which remain a challeng...

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

“…Our previous study confirmed that this circadian rhythm existed, and that the ratio of UH2/Ura in plasma was correlated with DPD levels in the liver of CRC rats [16]. Furthermore, by plotting the CL tot and AUC 0-∞ after single or repeated 5-FU administration to CRC ratsagainsttheratioofUH2/Urainplasma,measured before the PK experiments, a linear relationship was inferred [16]. Boisdron-Celle et al reported that measuring the UH2/Ura ratio appeared to be the single best method for determining DPD deficiency and activity level for clinical use [30].…”

“…reported that the levels of DPD in rat liver were highest at around noon and lowest at around midnight , indicating that rat DPD levels peaked during rest time and declined at active times. Our previous study confirmed that this circadian rhythm existed, and that the ratio of UH2/Ura in plasma was correlated with DPD levels in the liver of CRC rats . Furthermore, by plotting the CL tot and AUC 0‐∞ after single or repeated 5‐FU administration to CRC rats against the ratio of UH2/Ura in plasma, measured before the PK experiments, a linear relationship was inferred .…”

“…5‐FU bolus injections administered to CRC rats at different times of day yielded a significant decrease in CL tot and increase of AUC 0‐∞ on day 7, compared with that on day 1 (Figure and Table ). It was reported previously that 5‐FU PK parameters exhibited circadian variation in CRC rats , whereby the i.v. 5‐FU bolus administered at different times of day yielded significant circadian variations in CL tot and AUC 0‐∞ on day 1, although the PK parameters of subsequent 5‐FU administration showed no circadian variation, consistent with the findings of the present study.…”

“…To predict DPD activity from the observed plasma UH2/Ura ratio, the regression model was selected on the basis of the coefficient of determination (r 2 ) and the results showed that quadratic regression curve (DPD activity = 11.23 · (UH2/Ura) 2 -0.968 · (UH2/Ura) + 0.040, r 2 = 0.865) was applied ( Figure 3). Pharmacokinetic parameters were obtained from the plasma concentration-time curve of 5-FU after intravenous administration of 5-FU (20 mg/kg) to rats with colorectal cancer (CRC) at 7 am, 1 pm, or 7 pm hours for 1, 3, or 7 days ( Figure 1 and Table 1) variation in CRC rats [16], whereby the i.v. 5-FU bolus administered at different times of day yielded significant circadian variations in CL tot and AUC 0-∞ on day 1, although the PK parameters of subsequent 5-FU administration showed no circadian variation, consistent with the findings of the present study.…”

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).…”