Effects of a bolus injection of 5-fluorouracil on dihydropyrimidine dehydrogenase activity in rats receiving continuous infusion of 5-fluorouracil.

PURPOSE: The options for improving the chemotherapeutic regimen consisting of bolus plus infusion of 5-fluorouracil (5-FU) include omitting the 5-FU bolus injection. We examined the effects of a 5-FU bolus injection on the activity of dihydropyrimidine dehydrogenase (DPD), which is the first and rate-limiting enzyme of 5-FU catabolism, in rats.

METHODS: The rats were divided into three groups, and then continuous infusion (50 mg/m(2)/h) for 4 h was started with a bolus injection of saline, 20 mg/kg 5-FU, or 60 mg/kg 5-FU. Plasma 5-FU, uracil (Ura), dihydrouracil (UH2) levels, and hepatic DPD activity were determined after administration of 5-FU.

RESULTS: The half-life after the end of the infusion (t 1/2, 4-8 h) of 5-FU in the rats given the bolus injection was significantly longer than in those that had been given saline, and it increased with increasing 5-FU bolus injection dosage (r = 0.801, p < 0.01). The plasma UH2/Ura ratio, an indirect biomarker of hepatic DPD activity, tended to be lower in the rats that had received a 5-FU bolus injection than in those that had not, and it remained low after infusion ended. The hepatic DPD activity in rats that had received a 5-FU bolus injection was significantly lower than in those that had not. Negative correlation was observed between DPD activity and bolus injection dosage (r = -0.691, p < 0.05).

CONCLUSIONS: A bolus injection suppresses hepatic DPD activity and its effects are dependent on dosage, resulting in slower elimination of 5-FU from the blood and contributing to long-term systemic exposure to 5-FU.