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 1 255 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 2.557 1 μg·mL-1·h, 1.629 2 μg·g-1·h and 2.085 0 μg·g-1·h, and T1/2 was 0.782 3 h, 1.528 1 h and 1.289 6 h in plasma, tumor, and healthy tissue, respectively. The AUCs of 5-FU were 0.418 7 μg·mL-1 h, 1.671 7 μg·g-1·h and 1.020 8 μg·g-1·h; the T1/2 was 0.631 3 h ,1.204 1 h and 1.031 2 h in plasma, tumor, and healthy tissue, respectively. The tissue distribution factors of capecitabine were 0.637 1 in tumor (AUCcap-Tumor/AUCcap-plasma) and 0.851 4 in healthy tissue (AUCcap-HT/AUCcap-plasma). The tissue distribution factors of 5-FU were 3.992 6 in tumor (AUC5-FU-tumor/AUC5-FU-plasma) and 2.438 0 in healthy tissue (AUC5-FU-HT/AUC5-FU-plasma). The AUC ratios of 5-FU to capecitabine were 0.1637, 1.0261, and 0.489 5 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.%目的 描述卡培他滨在血浆、乳腺肿瘤组织和正常组织中向氟脲嘧啶转化的药物动力学过程.方法 27名乳腺癌化疗患者口服卡培他滨 1 255 mg·m-2,同步采集血浆、肿瘤组织和相邻正常组织样品,并用HPLC法测定卡培他滨和5-FU的浓度.使用自建的药物动力学模型拟合卡培他滨和5-FU的药时曲线,并利用拟合参数计算血浆和乳腺组织中卡培他滨和5-FU的组织分布因子,以及卡培他滨向5-FU的转化率.结果 卡培他滨在肿瘤组织中的组织分布因子(AUCTumor/AUCplasma)为0.637 1,正常组织中的组织分布因子(AUCH-tissue/AUCplasma)为0.851 4;5-FU在乳腺肿瘤的组织分布因子AUCTumor/AUCplasma为3.992 6,正常组织的组织分布因子AUCH-tissue/AUCplasma为 2.438 0.卡培他滨向5-FU的转化率在肿瘤、邻近正常组织和血浆中分别为1.026、0.489 5和 0.163.结论 血浆、乳腺肿瘤组织和相邻正常组织的药时曲线拟合对卡培他滨转化为5-FU及5-FU消除过程进行了较好的描述.卡培他滨在血浆、乳腺肿瘤组织和相邻正常组织中的分布较为接近,其活性代谢产物5-FU在肿瘤组织中分布为血浆的10.14倍,为正常组织的3.41倍.卡培他滨在肿瘤组织中向5-FU的转化率较高.
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