Pharmacokinetic effects of curcumin on docetaxel mediated by OATP1B1, OATP1B3 and CYP450s

Xiaolin Sun; Junxiu Li; Chaorui Guo; Han Xing; Jie Xu; Yanli Wen; Zhixia Qiu; Qiuyang Zhang; Yi Zheng; Xijing Chen; Di Zhao

doi:10.1016/j.dmpk.2016.02.005

Pharmacokinetic effects of curcumin on docetaxel mediated by OATP1B1, OATP1B3 and CYP450s

Drug Metab Pharmacokinet. 2016 Aug;31(4):269-75. doi: 10.1016/j.dmpk.2016.02.005. Epub 2016 Mar 11.

Authors

Xiaolin Sun¹, Junxiu Li², Chaorui Guo³, Han Xing⁴, Jie Xu⁵, Yanli Wen⁶, Zhixia Qiu⁷, Qiuyang Zhang⁸, Yi Zheng⁹, Xijing Chen¹⁰, Di Zhao¹¹

Affiliations

¹ Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: [email protected].
² Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: [email protected].
³ Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: [email protected].
⁴ Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: [email protected].
⁵ Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: [email protected].
⁶ Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: [email protected].
⁷ Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: [email protected].
⁸ Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: [email protected].
⁹ Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: [email protected].
¹⁰ Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: [email protected].
¹¹ Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu 210009, China. Electronic address: [email protected].

PMID: 27452633
DOI: 10.1016/j.dmpk.2016.02.005

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.

Keywords: Curcumin; Docetaxel; Human liver microsomes; OATP1B1; OATP1B3; Pharmacokinetics.

MeSH terms

Animals
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacokinetics*
Curcumin / pharmacology*
Docetaxel
Drug Interactions
HEK293 Cells
Humans
Kinetics
Liver-Specific Organic Anion Transporter 1 / antagonists & inhibitors
Liver-Specific Organic Anion Transporter 1 / metabolism*
Male
Microsomes, Liver / enzymology
Organic Anion Transporters, Sodium-Independent / antagonists & inhibitors
Organic Anion Transporters, Sodium-Independent / metabolism*
Rats, Sprague-Dawley
Taxoids / metabolism
Taxoids / pharmacokinetics*

Substances

Antineoplastic Agents
Liver-Specific Organic Anion Transporter 1
Organic Anion Transporters, Sodium-Independent
Taxoids
Docetaxel
Curcumin