Impact of curcumin on the pharmacokinetics of rosuvastatin in rats and dogs based on the conjugated metabolites

Abstract

1. Plasma concentrations of curcumin-O-glucuronide (COG) and curcumin-O-sulfate (COS) significantly increased after Sprague-Dawley rats dealt with the Oatp inhibitor rifampicin, with the C_max ascending 2.9 and 6.7 times, and the AUC_0–∞ ascending 4.4 and 10.8 times, respectively. When pretreated with the Oat inhibitor probenecid, the C_max increased 4.4 and 20 times, and the AUC_0–∞ increased 3.2 and 13.9 times, respectively. The results suggested that COG and COS may be the substrates of Oatp and Oat.

2. The accumulation of curcumin significantly increased in organic anion transporting polypeptide (OATP)- and organic anion transporter (OAT)-transfected human embryonic kidney (HEK) 293 systems, which suggested that curcumin was a substrate of OATP1B1, OATP1B3, OATP2B1, OAT1, and OAT3; and COG was a substrate of OATP1B1, OATP1B3, and OAT3.

3. Inhibition study using rosuvastatin as the substrate in OATP1B1- and OATP1B3-transfected cells indicated that curcumin was an OATP1B1 and 1B3 inhibitor, with IC₅₀ at 5.19 ± 0.05 and 3.68 ± 0.05 μM, respectively; the data for COG were 1.04 ± 0.01 and 1.08 ± 0.02 μM, respectively. COS was speculated to be an inhibitor of hepatic OATP1B1 as calculated using the ADMET Predictor.

4. COG and COS are substrates and inhibitors of OATP/Oatp. Co-administration of curcumin significantly increased rosuvastatin concentration in rat and dog plasma.

• Curcumin
• drug–drug interaction
• OAT
• OATP
• rosuvastatin
• transporter

Acknowledgements

The authors would like to thank Guiying Chen, Guangjie Yang, Wenyi Li, Fei Hu, Ying Li, Mengli Wang, and Lei Li for their supports in animal experiments and sample analyses. The authors would also like to thank Professor Yueming Ma (Laboratory of Pharmacokinetics, Shanghai University of Traditional Chinese Medicine, Shanghai, China) for the kind supply of the ADMET Predictor.

Declaration of interest

We declare that we have no conflicts of interest.

This work was supported by the China Postdoctoral Science Foundation (Grant No. 2014M552050).

Supplementary material available online