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Inhibition of the organic anion‐transporting polypeptide 1B1 by quercetin: an in vitro and in vivo assessment
Author(s) -
Wu LanXiang,
Guo ChengXian,
Chen WangQing,
Yu Jing,
Qu Qiang,
Chen Yao,
Tan ZhiRong,
Wang Guo,
Fan Lan,
Li Qing,
Zhang Wei,
Zhou HongHao
Publication year - 2012
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2011.04150.x
Subject(s) - in vivo , in vitro , chemistry , quercetin , organic anion transporting polypeptide , pharmacology , biochemistry , medicine , biology , microbiology and biotechnology , transporter , gene , antioxidant
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • OATP1B1 is a liver‐specific expression drug transporter and mediates the uptake of a broad range of compounds into hepatocytes. Modulation the activity of OATP1B1 may alter the pharmacokinetics of its substrate drugs, causing potential drug–drug interactions. As a popular dietary supplement in the United States, quercetin has been shown to interact with some drug transporters and efficiently influences their activity, but the effect of quercetin on OATP1B1 activity is not well known. WHAT THIS STUDY ADDS • Quercetin inhibits the OATP1B1‐mediated transport of E3S and pravastatin in vitro , and also has a modest inhibitory influence on the pharmacokinetics of pravastatin in healthy Chinese‐Han male volunteers. AIM To investigate the effect of quercetin on organic anion transporting polypeptide 1B1 (OATP1B1) activities in vitro and on the pharmacokinetics of pravastatin, a typical substrate for OATP1B1 in healthy Chinese‐Han male subjects. METHODS Using human embryonic kidney 293 (HEK293) cells stably expressing OATP1B1, we observed the effect of quercetin on OATP1B1‐mediated uptake of estrone‐3‐sulphate (E3S) and pravastatin. The influence of quercetin on the pharmacokinetics of pravastatin was measured in 16 healthy Chinese‐Han male volunteers receiving a single dose of pravastatin (40 mg orally) after co‐administration of placebo or 500 mg quercetin capsules (once daily orally for 14 days). RESULTS Quercetin competitively inhibited OATP1B1‐mediated E3S uptake with a K i value of 17.9 ± 4.6 µ m and also inhibited OATP1B1‐mediated pravastatin uptake in a concentration dependent manner (I C 50 , 15.9 ± 1.4 µ m ). In healthy Chinese‐Han male subjects, quercetin increased the pravastatin area under the plasma concentration – time curve (AUC(0,10 h) and the peak plasma drug concentration ( C max ) to 24% (95% CI 15, 32%, P < 0.001) and 31% (95% CI 20, 42%, P < 0.001), respectively. After administration of quercetin, the elimination half‐life ( t 1/2 ) of pravastatin was prolonged by 14% (95% CI 4, 24%, P = 0.027), with no change in the time to reach C max ( t max ). Moreover, quercetin decreased the apparent clearance (CL/ F ) of pravastatin by 18% (95% CI 75, 89%, P < 0.001). CONCLUSIONS These findings suggest that quercetin inhibits the OATP1B1‐mediated transport of E3S and pravastatin in vitro and also has a modest inhibitory influence on the pharmacokinetics of pravastatin in healthy Chinese‐Han male volunteers. The effects of quercetin on other OATP1B1 substrate drugs deserve further investigation.