Premium
Glycyrrhizin has a high likelihood to be a victim of drug–drug interactions mediated by hepatic organic anion‐transporting polypeptide 1B1/1B3
Author(s) -
Dong Jiajia,
Olaleye Olajide E,
Jiang Rongrong,
Li Jing,
Lu Chuang,
Du Feifei,
Xu Fang,
Yang Junling,
Wang Fengqing,
Jia Weiwei,
Li Chuan
Publication year - 2018
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14393
Subject(s) - glycyrrhizin , multidrug resistance associated protein 2 , pharmacology , pharmacokinetics , organic anion transporting polypeptide , physiologically based pharmacokinetic modelling , organic anion transporter 1 , chemistry , abcg2 , bile salt export pump , excretion , transporter , drug , biochemistry , atp binding cassette transporter , medicine , gene
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.