Sun Xiaolin, Li Junxiu, Guo Chaorui, Xing Han, Xu Jie, Wen Yanli, Qiu Zhixia, Zhang Qiuyang, Zheng Yi, Chen Xijing, Zhao Di
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
Drug Metab Pharmacokinet. 2016 Aug;31(4):269-75. doi: 10.1016/j.dmpk.2016.02.005. Epub 2016 Mar 11.
Curcumin can synergistically enhance docetaxel's in vitro and in vivo antitumor activity and has been co-administrated with docetaxel in clinical trials. The aim of our study is to investigate the effect of curcumin on the pharmacokinetics of docetaxel and explore its mechanism on OATP1B1, OATP1B3 and human liver microsomes (HLMs). In rats, curcumin increased the docetaxel area under the plasma concentration-time curve (AUC0-8h) and the terminal half-life (t1/2) to 1.86- and 1.55-fold, respectively. Moreover, curcumin decreased the clearance (CL) of docetaxel to 52.1%. Human embryonic kidney 293 (HEK293) cells stably expressing OATP1B1 and OATP1B3 were used to observe the effects of curcumin on OATP1B1 and OATP1B3-mediated uptake of docetaxel. Curcumin exhibited potent inhibition on OATP1B1 and OATP1B3-mediated docetaxel uptake with IC50 values of 3.81 ± 1.19 μM and 33.70 ± 1.22 μM, respectively. The inhibition of curcumin on docetaxel metabolism in HLMs indicated that curcumin can modestly inhibit the metabolism of docetaxel with the IC50 value of 22.70 ± 1.13 μM and Ki value of 24.72 ± 4.24 μM. The preclinical and clinical improved docetaxel's therapeutic efficacy when co-administrated with curcumin may be due to the inhibition of curcumin on OATP1B1, OATP1B3 and HLMs activities. Close attention should be paid when combined treatment with docetaxel and curcumin carried out clinically.
姜黄素可协同增强多西他赛的体外和体内抗肿瘤活性，并且在临床试验中已与多西他赛联合使用。我们研究的目的是调查姜黄素对多西他赛药代动力学的影响，并探索其对有机阴离子转运多肽1B1（OATP1B1）、有机阴离子转运多肽1B3（OATP1B3）和人肝微粒体（HLMs）的作用机制。在大鼠中，姜黄素使多西他赛的血浆浓度-时间曲线下面积（AUC0-8h）和末端半衰期（t1/2）分别增加至1.86倍和1.55倍。此外，姜黄素使多西他赛的清除率（CL）降低至52.1%。利用稳定表达OATP1B1和OATP1B3的人胚肾293（HEK293）细胞来观察姜黄素对OATP1B1和OATP1B3介导的多西他赛摄取的影响。姜黄素对OATP1B1和OATP1B3介导的多西他赛摄取表现出强效抑制作用，其半数抑制浓度（IC50）值分别为3.81± 1.19 μM和33.70± 1.22 μM。姜黄素对HLMs中多西他赛代谢的抑制作用表明，姜黄素可适度抑制多西他赛的代谢，其IC50值为22.70± 1.13 μM，抑制常数（Ki）值为24.72± 4.24 μM。临床前和临床研究表明，姜黄素与多西他赛联合使用时可提高多西他赛的治疗效果，这可能是由于姜黄素对OATP1B1、OATP1B3和HLMs活性的抑制作用。临床上在进行多西他赛和姜黄素联合治疗时应密切关注。
