Abstract: Aim To measure the penetration of capecitabine from the plasma into tissue and to investigate the pharmacokinetics of its metabolizing into fluorouracil (5-FU) in patients with advanced breast cancer. Methods Twenty-seven patients with breast cancer received repeated doses of 1255 mg·m^-2 of capecitabine twice daily for 7 d. Blood, tumor, and adjacent healthy tissue samples were collected. The concentrations of capecitabine and its metabolite 5-FU were determined by HPLC. The concentration-time profiles of capecitabine and 5-FU were fitted by pharmacokinetic model. The tissue distribution factors for capecitabine and 5-FU, and the AUC ratios of 5-FU to capecitabine in plasma, tumor or adjacent healthy tissue, were calculated with pharmacokinetic parameters, respectively. Results The Ka of capecitabine was 1.17 h^-1 in plasma, 0.46 h^-1 in tumor tissue, and 0.61 h^-1 in healthy tissue. The AUCs of capecitabine were 2.5571 μg·mL^-1·h, 1.6292 μg·g^-1·h and 2.0850 μg·g^-1·h, and T_1/2 was 0.7823 h, 1.5281 h and 1.2896 h in plasma, tumor, and healthy tissue, respectively. The AUCs of 5-FU were 0.4187 μg·mL^-1·h, 1.6717 μg·g^-1 ·h and 1.0208 μg·g^-1 ·h; the T_1/2 was 0.6313 h , 1.2041 h and 1.0312 h in plasma, tumor, and healthy tissue, respectively. The tissue distribution factors of capecitabine were 0.6371 in tumor (AUC_cap-Tumor/AUC_cap-plasma) and 0.8514 in healthy tissue (AUC_cap-HT/AUC_cap-plasma). The tissue distribution factors of 5-FU were 3.992 6 in tumor (AUC_5-FU-tumor/AUC_5-FU-plasma) and 2.4380 in healthy tissue (AUC_5-FU-HT/AUC_5-FU-plasma). The AUC ratios of 5-FU to capecitabine were 0.1637, 1.0261, and 0.4895 in plasma, tumor, and healthy tissue, respectively. Conclusion The simulation curves for the disposition of capecitabine and its metabolite 5-FU in plasma and tissue basically describe the activation process of capecitabine metabolizing to 5-FU and 5-FU elimination. There are similar distributions for capecitabine in plasma, tumor, and healthy tissue. The exposure of 5-FU in tumor was found to be 3.992 6 times greater than that in plasma and 2.438 0 times greater than that in healthy tissue. Capecitabine may metabolize preferentially to 5-FU in tumor tissue after oral administration.

Key words: capecitabine, capecitabine, pharmacokinetics, pharmacokinetics, 5-FU, 5-FU, tissue distribution factors, tissue distribution factors