Pharmacokinetics of 5-fluorouracil and increased hepatic dihydropyrimidine dehydrogenase activity levels in 1,2-dimethylhydrazine-induced colorectal cancer model rats

Abstract

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.

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

“…investigated the distribution of colon‐specific sodium alginate microspheres containing 5‐FU in the gastrointestinal tract, and performed PK and pharmacodynamic (PD) studies in CRC rats . It was reported previously that activated DPD levels in the liver would be induced by CRC and could be evaluated by the measurement of the plasma ratio of UH2/Ura, which is a possible surrogate biomarker of hepatic DPD activity in CRC rats . Moreover, 5‐FU PK and PD studies were conducted using DPD circadian variation in CRC rats and a pharmacokinetic‐pharmacodynamic (PK‐PD) model was developed with the value of the plasma ratio of UH2/Ura determined before 5‐FU treatment, to simulate tumor growth in rats with CRC after 5‐FU treatment .…”

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, ).…”

“…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, ).…”