The effect of dietary protein depletion on hepatic 5-fluorouracil metabolism.

Abstract

This study investigated the mechanism of protein depletion and its effect on host toxicity to 5‐fluorouracil. The effects of protein malnutrition on the hepatic metabolism of 5‐fluorouracil were examined using 19F‐nuclear magnetic resonance spectroscopy, pharmacokinetic disposition of 5‐fluorouracil, and hepatic dihydropyrimidine dehydrogenase activity. Harlan Sprague‐Dawley rats were given 5‐fluorouracil (150 mg/kg) by intraperitoneal injection after receiving normal (21.5%) or low (2.5%) protein diets for 19 to 30 days (mean, 25 days). Toxicity was assessed by weight loss, lymphocyte count, and survival. Hepatic fluorine spectra were used to evaluate the time to achieve maximum 5‐fluorouracil concentration, apparent hepatic 5‐fluorouracil half‐life, duration of detectable 5‐fluorouracil concentrations, and time to reach peak fluoro‐β‐alanine concentration (the main 5‐fluorouracil degradation product). Parallel experiments determined the pharmacokinetic disposition of 5‐fluorouracil and the hepatic dihydropyrimidine dehydrogenase activity.In the low‐protein group, the initial detection of the degradation product fluoro‐β‐alanine and the mean duration of 5‐fluorouracil signal in the liver were significantly prolonged: time to reach peak fluoro‐β‐alanine (minutes) 62 ± 39 vs 24 ± 12 (p <.05) and apparent 5‐fluorouracil half‐life (minutes) 96 ± 63 vs 42 ± 22 (p <.001). The 5‐fluorouracil clearance and the hepatic dihydropyrimidine dehydrogenase activity were also significantly lower in the low‐protein group: 1.8 ± 0.8 L/h/kg vs 7.3 ± 2.1 Llhlkg (p <.05) and 0.29 ± 0.04 U/mg of protein vs 0.37 ± 0.04 U/mg of protein (p <.05), respectively. Compared with animals fed a normal diet, animals in the low‐protein group sustained greater weight loss (g) 36 ± 17 vs 16 ± 17 (p <.05), lower lymphocyte count (mm3) 1767 ± 993 vs 5575 ± 2239 (p <.05), and greater mortality 7 days after 5‐fluorouracil (8/9 vs 1/10) (p <.01).