Penetration of capecitabine and its metabolites into malignant and healthy tissues of patients with advanced breast cancer

Capecitabine is an oral prodrug of 5-fluorouracil (FU). Since FU concentrations achieved in malignant lesions are an important determinant of efficacy, we investigated the intratumoral transcapillary transfer of capecitabine and its metabolites in vivo. A total of 10 patients with skin metastases from breast cancer received a daily dose of 2500 mg m(−2) capecitabine administered orally in two divided doses for 2 weeks. Microdialysis probes were inserted into a cutaneous metastasis and subcutaneous connective tissue to evaluate the interstitial tissue pharmacokinetics of capecitabine and its metabolites 5′-deoxy-5-fluorocytidine (DFCR), 5′-deoxy-5-fluorouridine (DFUR), and FU by capillary electrophoresis. As intended with the prodrug design of capecitabine, FU was present in low concentrations in tumour interstitium (median c(max): 0.26 μg ml(−1)) when compared with capecitabine, DFCR, and DFUR (median c(max): 2.66, 4.22, and 2.13 μg ml(−1), respectively). Capecitabine and its metabolites easily penetrated malignant and healthy tissue and equilibrated within 45 min between plasma and tissue interstitium. Considering tissue exposure at the extracellular level, no significant differences between healthy and malignant tissues were observed. Our data show that absorption and metabolism determined the tissue pharmacokinetics of capecitabine. There was no evidence of drug tolerance, which may be attributed to impaired transcapillary transfer into tissue, even after repeated administration as shown for three patients.