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...

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.

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To investigate the hepatic dihydropyrimidine dehydrogenase (DPD) activity in colorectal cancer (CRC), which is critically important to create a patient-specific dosing regimen, we performed 5-FU pharmacokinetic studies in 1,2-dimethylhydrazine-induced CRC model rats (CRC rats). After rats received 5-FU intravenous (IV) bolus injections, the area under the plasma concentration-time curve (AUC) and elimination half-life (t 1/2) in CRC rats (10.02 ± 0.37 μg h mL(-1), 0.30 ± 0.02 h, respectively) were significantly lower than that in control rats (13.46 ± 1.20 μg h mL(-1), 0.52 ± 0.05 h, respectively), whereas total plasma clearance (CLtot) in CRC rats (2.01 ± 0.07 L h(-1) kg(-1)) was significantly increased compared with that in control rats (1.54 ± 0.14 L h(-1) kg(-1)). Conversely, the avoidance ratio of the hepatic first-pass effect was approximately 20 % lower than that in control rats. Of interest is that hepatic DPD activity levels and the dihydrouracil-uracil ratio (UH2/Ura ratio) in plasma, which may act as a potential biomarker to evaluate hepatic DPD activity levels, were significantly increased in CRC rats. These results suggest that the decrease of hepatic availability in CRC rats is brought about by the increase in intrinsic clearance induced by the increase in DPD activity, resulting in a decrease in AUC and t 1/2 and an increase in CLtot after 5-FU IV bolus injection. Along with a proper dosing regimen for patients with CRC, a hepatic DPD activity monitoring system, such as the determination of UH2/Ura ratio in plasma, is desirable.