替加氟乳腺组织穿透及向氟尿嘧啶转化的药动学研究

Pharmacokinetic Analysis on Tissue Penetration of Tegafur and Tumor-Selective Distribution of 5-FU in Patients with Advanced Breast Cancer

目的描述替加氟在血浆、乳腺肿瘤组织和正常组织中向氟尿嘧啶(5-FU)转化的药动学过程。方法39名乳腺癌化疗病人po替加氟200 mg,同步采集血浆、肿瘤组织和相邻正常组织样品,并用HPLC测定替加氟和5-FU的浓度。使用自建的药动学模型拟合替加氟和5-FU的药-时曲线,并利用拟合参数计算血浆和乳腺组织中替加氟和5-FU的组织分布因子,以及替加氟向5-FU的转化率。结果替加氟在肿瘤、邻近正常组织和血浆中的AUC分别为51.20,59.28μg.h.g-1和156.44μg.h.g-1;半衰期分别为11.22,11.30和11.92 h。5-FU在肿瘤、邻近正常组织和血浆中的AUC分别为4.25,2.87μg.h.g-1和1.68 mg.h.L-1。替加氟在正常组织中的组织分布因子(AUCTum or/AUCp lasm a)为0.33,肿瘤组织中的组织分布因子(AUCH-tissue/AUCp lasm a)为0.38;5-FU在乳腺肿瘤的组织分布因子AUCTum or/AUCp lasm a为2.53,正常组织的组织分布因子AUCH-tissue/AUCp lasm a为1.71。结论血浆、乳腺肿瘤组织和相邻正常组织的药-时曲线拟合对替加氟转化为5-FU及5-FU消除过程进行了较好的描述。替加氟在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2.53倍,为正常组织的1.71倍。替加氟在肿瘤组织中向5-FU的转化率较高。

OBJECTIVE To evaluate the pharmacokinetic parameters of tegafur being metabolized into fluorouracil （5-FU） in patients with advanced breast cancer, and compare their characteristics of tissue distribution. METHODS 39 Patients with breast cancer were enrolled and received repeated doses of 200 mg tegafur twice daily. Plasma, tumor and adjacent healthy tissue samples were collected. The concentrations of tegafur and its metabolite 5-FU were determined by HPLC. The concentration-time profiles for tegafur and 5-FU were fitted with pharmacokinetic model constructed with characteristic metabolism. The tissue distribution factors for tegafur and 5-FU, and the AUC ratios of tegafur to 5-FU in plasma/tumor/healthy tissue were calculated, respectively. RESULT The AUCall of tegafur in tumor, healthy tissue and plasma were 51.20, 59. 28 μg · h · g^-1 and 156. 44 mg · h · L^-1 ,t1/2 were 11.22, 11.30 and 11.92 h, respectively. The AUCall of 5-FU in tumor, healthy tissue and plasma were 4. 25,2.87 μg · h· g^-1 and 1.68 mg· h · L^-1 , respectively. The tissue distribution factors of tegafur were 0. 33 in tumor （AUCTumor/AUCTumor） and 0. 38 in healthy tissue （AUCH-tissue/AUCplasma）. The tissue distribution factors of 5-FU were 2. 53 in tumor and 1.71 in healthy tissue. The AUC ratios of tegafur to 5-FU in tumor/healthy tissue/plasma were 8.30, 4. 84 and 1.07, respectively. CONCLUSION The simulated concentration-time curves of tegafur and its metabolite in plasma and tissue basically describe the activation process of tegafur into 5-FU and 5-FU elimination. The exposures of tegafur in tumor and healthy tissue are similar. The exposure of 5-FU in tumor is found to be 2. 53 times as much as that in plasma. It suggests that tegafur is preferentially metabolized into 5-FU in tumor tissue after oral administration.