Glycyrrhizin has a high likelihood to be a victim of drug-drug interactions mediated by hepatic organic anion-transporting polypeptide 1B1/1B3

doi:10.1111/bph.14393

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	Glycyrrhizin has a high likelihood to be a victim of drug-drug interactions mediated by hepatic organic anion-transporting polypeptide 1B1/1B3
	Dong, Jiajia 2,3; Olaleye, Olajide E.3; Jiang, Rongrong 3; Li, Jing3 ; Lu, Chuang 1; Du, Feifei 3; Xu, Fang 3; Yang, Junling3 ; Wang, Fengqing 3; Jia, Weiwei 3
刊名	BRITISH JOURNAL OF PHARMACOLOGY
	2018-09
卷号	175 期号:17 页码:3486-3503
ISSN号	0007-1188
DOI	10.1111/bph.14393
文献子类	Article
英文摘要	BACKGROUND AND PURPOSE Intravenous glycyrrhizin, having anti-inflammatory and hepatoprotective properties, is incorporated into the management of liver diseases in China. This investigation was designed to elucidate the molecular mechanism underlying hepatobiliary excretion of glycyrrhizin and to investigate its potential for drug-drug interactions on organic anion-transporting polypeptide (OATP)1B. EXPERIMENTAL APPROACH Human transporters mediating hepatobiliary excretion of glycyrrhizin were characterized at the cellular and vesicular levels and compared with rat hepatic transporters. The role of Oatp1b2 in glycyrrhizin's elimination and pharmacokinetics was evaluated in rats using the inhibitor rifampin. A physiologically based pharmacokinetic (PBPK) model for glycyrrhizin, incorporating transporter-mediated hepatobiliary excretion, was established and applied to predict potential drug-drug interactions related to glycyrrhizin in humans. KEY RESULTS Hepatobiliary excretion of glycyrrhizin involved human OATP1B1/1B3 (Oatp1b2 in rats)-mediated hepatic uptake from blood and human multidrug resistance-associated protein (MRP)2/breast cancer resistance protein (ABCP)/bile salt export pump (BSEP)/multidrug resistance protein 1 (Mrp2/Abcp/Bsep in rats)-mediated hepatic efflux into bile. In rats, rifampin impaired hepatic uptake of glycyrrhizin significantly increasing its systemic exposure. Glomerular-filtration-based renal excretion of glycyrrhizin was slow due to extensive protein binding in plasma. Quantitative analysis using the PBPK model demonstrated that OATP1B1/1B3 have critical roles in the pharmacokinetics of glycyrrhizin, which is highly likely to be a victim of drug-drug interactions when co-administered with potent dual inhibitors of these transporters. CONCLUSIONS AND IMPLICATIONS Transporter-mediated hepatobiliary excretion governs glycyrrhizin's elimination and pharmacokinetics. Understanding glycyrrhizin's potential drug-drug interactions on OATP1B1/1B3 should enhance the therapeutic outcome of glycyrrhizin-containing drug combinations on liver diseases.
资助项目	National Science & Technology Major Project of China 'Key New Drug Creation and Manufacturing Program'[2009ZX09304-002] ; National Science & Technology Major Project of China 'Key New Drug Creation and Manufacturing Program'[2017ZX09301012-006] ; National Science Foundation of China for Distinguished Young Scholars[30925044] ; National Natural Science Foundation of China[81603380]
WOS关键词	PRESYSTEMIC METABOLISM ; MOLECULAR-MECHANISMS ; HEALTHY-VOLUNTEERS ; MASS-SPECTROMETRY ; COMPOUND SUBJECT ; PHARMACOKINETICS ; ACID ; EXPOSURE ; PROTEIN ; AGENTS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	WILEY
WOS记录号	WOS:000441275100004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279604]
专题	上海药物代谢研究中心中科院受体结构与功能重点实验室新药研究国家重点实验室科研与新药推进处
通讯作者	Jia, Weiwei; Li, Chuan
作者单位	1.Sanofi, Dept DMPK, Cambridge, MA USA 2.Chinese Acad Sci, Univ Chinese Acad Sci, Beijing, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China;
推荐引用方式 GB/T 7714	Dong, Jiajia,Olaleye, Olajide E.,Jiang, Rongrong,et al. Glycyrrhizin has a high likelihood to be a victim of drug-drug interactions mediated by hepatic organic anion-transporting polypeptide 1B1/1B3[J]. BRITISH JOURNAL OF PHARMACOLOGY,2018,175(17):3486-3503.
APA	Dong, Jiajia.,Olaleye, Olajide E..,Jiang, Rongrong.,Li, Jing.,Lu, Chuang.,...&Li, Chuan.(2018).Glycyrrhizin has a high likelihood to be a victim of drug-drug interactions mediated by hepatic organic anion-transporting polypeptide 1B1/1B3.BRITISH JOURNAL OF PHARMACOLOGY,175(17),3486-3503.
MLA	Dong, Jiajia,et al."Glycyrrhizin has a high likelihood to be a victim of drug-drug interactions mediated by hepatic organic anion-transporting polypeptide 1B1/1B3".BRITISH JOURNAL OF PHARMACOLOGY 175.17(2018):3486-3503.