Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients

Cancer Chemother Pharmacol. 2000;45(4):291-7. doi: 10.1007/s002800050043.


Purpose: [corrected] Capecitabine (Xeloda) is a novel fluoropyrimidine carbamate rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumors. The purpose of this study was to demonstrate the preferential activation of capecitabine, after oral administration, in tumor in colorectal cancer patients, by the comparison of 5-FU concentrations in tumor tissues, healthy tissues and plasma.

Methods: Nineteen patients requiring surgical resection of primary tumor and/or liver metastases received 1,255 mg/m2 of capecitabine twice daily p.o. for 5-7 days prior to surgery. On the day of surgery, samples of tumor tissue, adjacent healthy tissue and blood samples were collected simultaneously from each patient, 2 to 12 h after the last dose of capecitabine had been administered. Concentrations of 5-FU in various tissues and plasma were determined by HPLC. The activities of the enzymes (CD, TP and DPD) involved in the formation and catabolism of 5-FU were measured in tissue homogenates, by catabolic assays.

Results: The ratio of 5-FU concentrations in tumor to adjacent healthy tissue (T/H) was used as the primary marker for the preferential activation of capecitabine in tumor. In primary colorectal tumors, the concentration of 5-FU was on average 3.2 times higher than in adjacent healthy tissue (P = 0.002). The mean liver metastasis/healthy tissue 5-FU concentration ratio was 1.4 (P = 0.49, not statistically different). The mean tissue/plasma 5-FU concentration ratios exceeded 20 for colorectal tumor and ranged from 8 to 10 for other tissues.

Conclusions: The results demonstrated the preferential activation of capecitabine to 5-FU in colorectal tumor, after oral administration to patients. This is explained to a great extent by the activity of TP in colorectal tumor tissue, (the enzyme responsible for the conversion of 5'-DFUR to 5-FU), which is approximately four times that in adjacent healthy tissue. In the liver, TP activity is approximately equal in metastatic and healthy tissue, which explains the lack of preferential activation of capecitabine in these tissues.

Publication types

  • Clinical Trial
  • Multicenter Study

MeSH terms

  • Aged
  • Antimetabolites, Antineoplastic / metabolism*
  • Biotransformation
  • Capecitabine
  • Chromatography, High Pressure Liquid
  • Colon / metabolism
  • Colorectal Neoplasms / metabolism*
  • Cytidine Deaminase / metabolism
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / metabolism
  • Dihydrouracil Dehydrogenase (NADP)
  • Female
  • Fluorouracil / metabolism*
  • Humans
  • Liver / metabolism
  • Male
  • Middle Aged
  • Oxidoreductases / metabolism
  • Prodrugs / metabolism*
  • Rectum / metabolism
  • Spectrophotometry, Ultraviolet
  • Thymidine Phosphorylase / metabolism


  • Antimetabolites, Antineoplastic
  • Prodrugs
  • Deoxycytidine
  • Capecitabine
  • Oxidoreductases
  • Dihydrouracil Dehydrogenase (NADP)
  • Thymidine Phosphorylase
  • Cytidine Deaminase
  • Fluorouracil