Inhibition of the organic anion-transporting polypeptide 1B1 by quercetin: an in vitro and in vivo assessment.
Inhibition of the organic anion-transporting polypeptide 1B1 by quercetin: an in vitro and in vivo assessment.
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DOI：
10.1111/j.1365-2125.2011.04150.x
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发表时间：
2012-05
影响因子：
3.4
通讯作者：
Lan-Xiang Wu;Chengxian Guo;Wang-Qing Chen;Jing Yu;Q. Qu;Yao Chen;Z. Tan;Guo Wang;L. Fan;Qing Li;Wei Zhang-;Honghao Zhou
中科院分区：
文献类型：
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作者：
Lan-Xiang Wu;Chengxian Guo;Wang-Qing Chen;Jing Yu;Q. Qu;Yao Chen;Z. Tan;Guo Wang;L. Fan;Qing Li;Wei Zhang-;Honghao Zhou
目的 探讨槲皮素对健康汉族男性有机阴离子转运多肽 1B1 (OATP1B1) 体外活性以及对 OATP1B1 典型底物普伐他汀药代动力学的影响。方法 使用稳定表达 OATP1B1 的人胚肾 293 (HEK293) 细胞，我们观察了槲皮素对 OATP1B1 介导的雌酮 3-硫酸盐 (E3S) 和普伐他汀摄取的影响。在 16 名健康的中国汉族男性志愿者中测量了槲皮素对普伐他汀药代动力学的影响，这些志愿者在联合服用安慰剂或 500 mg 槲皮素胶囊（每天口服一次，持续 14 天）后接受单剂量普伐他汀（40 mg 口服）。结果槲皮素竞争性抑制OATP1B1介导的E3S摄取，K(i)值为17.9±4.6μm，并且还以浓度依赖性方式抑制OATP1B1介导的普伐他汀摄取(IC(50)，15.9±1.4μm)。在健康的中国汉族男性受试者中，槲皮素使普伐他汀的血浆浓度-时间曲线下面积（AUC（0.10 h）和血浆药物峰浓度（C（max））分别增加至24%（95% CI 15、32%，P < 0.001）和31%（95% CI 20、42%，P < 0.001）。槲皮素使普伐他汀的消除半衰期 (t(1/2) ) 延长 14% (95% CI 4, 24%, P = 0.027)，而达到 C(max) 的时间 (t(max) ) 没有变化。此外，槲皮素使普伐他汀的表观清除率 (CL/F) 降低 18% (95% CI 75, 89%, P <结论 这些研究结果表明，槲皮素在体外抑制 OATP1B1 介导的 E3S 和普伐他汀的转运，并且对健康中国汉族男性志愿者中普伐他汀的药代动力学也有一定的抑制作用。槲皮素对其他 OATP1B1 底物药物的影响值得进一步研究。
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 µm and also inhibited OATP1B1-mediated pravastatin uptake in a concentration dependent manner (IC(50) , 15.9 ± 1.4 µm). 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.