The effect of dietary protein depletion on hepatic 5‐Fluorouracil metabolism

Background. Protein calorie malnutrition, which is highly prevalent in tumor‐bearing hosts, increases toxicity to 5‐fluorouracil (5‐FU), but the mechanisms are unclear. This study investigated the effects of protein depletion on 5‐FU in vivo hepatic metabolism using F¹⁹‐nuclear magnetic resonance spectroscopy (¹⁹F‐NMRS). Methods. Rats received normal (21.5%) or low (2.5%) protein diet for 25 days. 5‐FU was injected intraperitoneally, and hepatic fluorine spectra were obtained. Parallel experiments were conducted to determine serum 5‐FU pharmacokinetics using high‐performance liquid chromatography (HPLC) and to measure hepatic dihydropyrimidine dehydrogenase (DPD) activity. Results. The mean time of initial detection of fluoro‐β‐alanine and the mean duration of the 5‐FU signal in the liver were significantly prolonged in the low‐protein group. 5‐FU clearance and hepatic DPD activity were significantly lower in the low‐protein group. Low‐protein animals demonstrated increased toxicity, with diarrhea, weight loss, leukopenia (P < 0.001), and an 85% mortality, compared with regular diet animals, who had mild diarrhea and weight loss but no leukopenia and a 12% mortality. Conclusion. Protein depletion results in increased toxicity to 5‐FU, which is associated with a significantly decreased rate of hepatic metabolism and clearance of 5‐FU and a significant decrease in hepatic DPD activity. ¹⁹F‐NMRS can noninvasively identify these alterations of 5‐FU metabolism in vivo and may serve as a useful guide to determining chemotherapy dosage adjustments to reduce toxicity.