The Hepatobiliary Disposition of Timosaponin B2 Is Highly Dependent on Influx/Efflux Transporters but Not Metabolism

doi:10.1124/dmd.114.059923

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	The Hepatobiliary Disposition of Timosaponin B2 Is Highly Dependent on Influx/Efflux Transporters but Not Metabolism
	Sheng, Jingjing 1; Tian, Xiaoting 3; Xu, Guanglin 1; Wu, Zhitao 3; Chen, Chen 2; Wang, Le 3; Pan, Lili 1; Huang, Chenggang3 ; Pan, Guoyu3
刊名	DRUG METABOLISM AND DISPOSITION
	2015-01
卷号	43 期号:1 页码:63-72
ISSN号	0090-9556
DOI	10.1124/dmd.114.059923
文献子类	Article
英文摘要	The purpose of this study was to characterize the hepatobiliary disposition of timosaponin B2 (TB-2), a natural saponin. Although TB-2 has multiple pharmacologic activities, the mechanism of its hepatobiliary disposition has not been explored. Because the metabolism of TB-2 is limited and the accumulation of TB-2 in primary hepatocytes is highly temperature dependent (93% of its accumulation is due to active uptake), the contribution of hepatic transporters was investigated. Organic anion-transporting polypeptide (OATP) 1B1- and OATP1B3-transfected human embryonic kidney 293 cells were employed. TB-2 serves as a substrate for OATP1B1 and OATP1B3, with the former playing a predominant role in the hepatic uptake of TB-2. An inhibition study in sandwich-cultured rat hepatocytes suggested that TB-2 is a substrate for both breast cancer resistance protein (Bcrp) and multidrug resistance-associated protein 2 (Mrp2), consistent with its high biliary excretion index (43.1-44.9%). This hypothesis was further verified in BCRP and MRP2 membrane vesicles. The cooperation of uptake and efflux transporters in TB-2 hepatic disposition could partially explain the double-peak phenomenon observed in rat plasma and liver and biliary clearance, which accounted for 70% of the total TB-2 clearance. Moreover, TB-2 significantly increased the rosuvastatin concentration in rat plasma in a concentration-dependent manner and decreased its biliary excretion, which corresponded to reductions in rosuvastatin accumulation in hepatocytes and the biliary excretion index in sandwich-cultured rat hepatocytes, representing a perfect example of a potential saponin-statin drug-drug interaction. These studies demonstrate that transporters (Oatp, Bcrp/Mrp2), but not metabolism, contribute significantly to rat TB-2 hepatobiliary disposition.
资助项目	State Key Program of National Natural Science Foundation of China[81030065] ; National Science Foundation of China[81302836] ; National Science Foundation of China[81274055] ; Major National Science and Technology Programs[2012ZX09301001-006] ; Major National Science and Technology Programs[2012ZX09302003] ; National High Technology Research and Development Program of China[2013AA032202]
WOS关键词	RESISTANCE-ASSOCIATED PROTEIN-2 ; DRUG-DRUG INTERACTIONS ; RAT HEPATOCYTES ; SUPEROXIDE GENERATION ; MEDIATED-TRANSPORT ; STEROIDAL SAPONINS ; BILIARY CLEARANCE ; MASS-SPECTROMETRY ; HEPATIC-UPTAKE ; PHARMACOKINETICS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000346186000009
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276787]
专题	上海中药现代化研究中心药物安全性评价中心
通讯作者	Pan, Guoyu
作者单位	1.Nanjing Normal Univ, Coll Life Sci, Key Lab Mol & Med Biotechnol, Nanjing, Jiangsu, Peoples R China; 2.Jiangsu Univ, Inst Life Sci, Zhenjiang, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Sheng, Jingjing,Tian, Xiaoting,Xu, Guanglin,et al. The Hepatobiliary Disposition of Timosaponin B2 Is Highly Dependent on Influx/Efflux Transporters but Not Metabolism[J]. DRUG METABOLISM AND DISPOSITION,2015,43(1):63-72.
APA	Sheng, Jingjing.,Tian, Xiaoting.,Xu, Guanglin.,Wu, Zhitao.,Chen, Chen.,...&Pan, Guoyu.(2015).The Hepatobiliary Disposition of Timosaponin B2 Is Highly Dependent on Influx/Efflux Transporters but Not Metabolism.DRUG METABOLISM AND DISPOSITION,43(1),63-72.
MLA	Sheng, Jingjing,et al."The Hepatobiliary Disposition of Timosaponin B2 Is Highly Dependent on Influx/Efflux Transporters but Not Metabolism".DRUG METABOLISM AND DISPOSITION 43.1(2015):63-72.