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.
We aimed to develop a simple pharmacokinetic-pharmacodynamic (PK-PD) model to predict the onset and degree of severe toxic side effects that severely limit the use of many anticancer agents, such as myelosuppression, in rats. Our PK-PD model consisted of a two-compartment PK model, with one compartment representing proliferative cells and some transit compartments consisting of maturing cells, while the other compartment represented circulating blood cells for the PD model. The semi-physiological PK-PD model effectively captured the features of myelosuppression and the degree of the off-target toxicities observed after 5-fluorouracil (5-FU) chemotherapy, and helped simultaneously simulate the whole time course for alterations in leukocyte, neutrophil and lymphocyte counts after 5-FU treatment in rats. Interestingly, by plotting the nadir period of leukocyte, neutrophil and lymphocyte counts as determined by PK-PD analytical simulation curves against the area under the plasma 5-FU concentration-time curve (AUC0-∞) after intravenous administration of 5-FU, a linear relationship was inferred, with r2=0.989, 0.877 and 0.956, respectively. The semi-physiological PK-PD model is a valuable tool for evaluating a variety of novel cancer chemopreventive agents or emerging therapeutic strategies that are difficult to address in humans.
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