Comparison of in vitro metabolic conversion of capecitabine to 5-FU in rats, mice, monkeys and humans--toxicological implications

J Toxicol Sci. 2011 Aug;36(4):411-22. doi: 10.2131/jts.36.411.


Capecitabine is an oral anticancer prodrug which is converted to 5-fluorouracil (5-FU) via 3 enzymatic steps, these being 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR), and finally 5-FU by carboxylesterase (CES), cytidine deaminase (CDA), and thymidine phosphorylase (TP), respectively. Because rats, mice and monkeys are used for preclinical safety studies, we investigated the in vitro conversion from capecitabine to 5-FU by hepatic and intestinal mucosal microsomes and cytosols, to compare their metabolic activity to that of humans. Capecitabine was hydrolyzed to 5'-DFCR in hepatic and intestinal mucosal microsomes in these animal species. In humans and monkeys, CL(int) (V(max)/K(m)) for the hydrolysis of capecitabine in intestine (expressed as µl/min/g tissue) was much lower than that in hepatic microsomes but, in rats and mice, CL(int) was higher in intestine than in liver. In humans and monkeys, similar K(m) values and inhibition patterns by tetrahydrouridine (THU) a CDA inhibitor, were observed in CDA activity of hepatic and intestinal cytosols. However, rats showed very low CDA activity and mice showed non-Michaelis-Menten kinetics and a different inhibition pattern by THU. K(m) values for TP activity were almost similar in rats, mice, monkeys and humans. In conclusion, it was confirmed that monkeys are a suitable animal model for the safety assessment of capecitabine in terms of metabolic enzymes and it was suggested that higher toxic incidences in mouse small intestine were related to high hydrolytic activity of capecitabine in the small intestine.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Biotransformation
  • Capecitabine
  • Carboxylesterase / metabolism
  • Chromatography, High Pressure Liquid
  • Cytidine Deaminase / metabolism
  • Cytosol / enzymology
  • Cytosol / metabolism
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / metabolism
  • Deoxycytidine / pharmacokinetics
  • Deoxycytidine / toxicity
  • Fluorouracil / analogs & derivatives*
  • Fluorouracil / metabolism
  • Fluorouracil / pharmacokinetics
  • Fluorouracil / toxicity
  • Humans
  • Hydrolysis
  • In Vitro Techniques
  • Intestinal Mucosa / enzymology
  • Intestinal Mucosa / metabolism*
  • Intestines / drug effects
  • Intestines / enzymology
  • Intestines / pathology
  • Liver / drug effects
  • Liver / enzymology
  • Liver / metabolism*
  • Liver / pathology
  • Macaca fascicularis
  • Male
  • Mice
  • Mice, Inbred Strains
  • Microsomes / enzymology
  • Microsomes / metabolism
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism
  • Prodrugs / metabolism
  • Prodrugs / pharmacokinetics*
  • Prodrugs / toxicity*
  • Rats
  • Rats, Sprague-Dawley
  • Species Specificity


  • Prodrugs
  • Deoxycytidine
  • Capecitabine
  • Carboxylesterase
  • Cytidine Deaminase
  • Fluorouracil