title: Pharmacokinetic effects of curcumin on docetaxel mediated by OATP1B1, OATP1B3 and CYP450s.
abstract: 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.
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: lynnsun_2013@hotmail.com.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Sun
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: pdssk999@163.com.
authors.forename: Junxiu
authors.initials: J
authors.lastname: Li
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: gcr1993@126.com.
authors.forename: Chaorui
authors.initials: C
authors.lastname: Guo
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: xinghankf@126.com.
authors.forename: Han
authors.initials: H
authors.lastname: Xing
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: xujie_1214@163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: mayday_88@163.com.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: qiuzhixia_cpu@163.com.
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: zqy_may@126.com.
authors.forename: Qiuyang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: Yzheng0822@163.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: chenxj-lab@hotmail.com.
authors.forename: Xijing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: zhaodihehe@126.com.
authors.forename: Di
authors.initials: D
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D003474:Curcumin / Q000494:pharmacology*; D000077143:Docetaxel; D004347:Drug Interactions; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D027381:Liver-Specific Organic Anion Transporter 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D043823:Taxoids / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D029362:Organic Anion Transporters, Sodium-Independent; D043823:Taxoids; D000077143:Docetaxel; D003474:Curcumin
keywords: Curcumin; Docetaxel; Human liver microsomes; OATP1B1; OATP1B3; Pharmacokinetics