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-beta-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.


CONCLUSIONS
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.
Davis
L E
LE
School of Pharmacy, Philadelphia College of Pharmacy and Science, Pennsylvania.
Lenkinski
R E
RE
Shinkwin
M A
MA
Kressel
H Y
HY
Daly
J M
JM
D000818:Animals; D004044:Dietary Proteins / Q000008:administration & dosage; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D008099:Liver / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010088:Oxidoreductases / Q000378:metabolism; D011502:Protein-Energy Malnutrition / Q000378:metabolism*; D051381:Rats; D011915:Rats, Inbred BUF
D004044:Dietary Proteins; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil