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Molecular mechanisms governing different pharmacokinetics of ginsenosides and potential for ginsenoside‐perpetrated herb–drug interactions on OATP 1 B 3
Author(s) -
Jiang Rongrong,
Dong Jiajia,
Li Xiuxue,
Du Feifei,
Jia Weiwei,
Xu Fang,
Wang Fengqing,
Yang Junling,
Niu Wei,
Li Chuan
Publication year - 2015
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.12971
Subject(s) - protopanaxadiol , ginsenoside , ginseng , chemistry , panax notoginseng , pharmacology , bile salt export pump , multidrug resistance associated protein 2 , pharmacokinetics , atp binding cassette transporter , biochemistry , transporter , biology , medicine , alternative medicine , pathology , gene
Background and Purpose Ginsenosides are bioactive saponins derived from P anax notoginseng roots ( S anqi) and ginseng. Here, the molecular mechanisms governing differential pharmacokinetics of 20( S )‐protopanaxatriol‐type ginsenoside R g 1 , ginsenoside R e and notoginsenoside R 1 and 20( S )‐protopanaxadiol‐type ginsenosides R b 1 , R c and R d were elucidated. Experimental Approach Interactions of ginsenosides with human and rat hepatobiliary transporters were characterized at the cellular and vesicular levels. A rifampin‐based inhibition study in rats evaluated the in vivo role of organic anion‐transporting polypeptide (O atp)1b2. Plasma protein binding was assessed by equilibrium dialysis. Drug–drug interaction indices were calculated to estimate potential for clinically relevant ginsenoside‐mediated interactions due to inhibition of human OATP 1 B s. Key Results All the ginsenosides were bound to human OATP 1 B 3 and rat O atp1b2 but only the 20( S )‐protopanaxatriol‐type ginsenosides were transported. Human multidrug resistance‐associated protein ( MRP )2/breast cancer resistance protein ( BCRP )/bile salt export pump ( BSEP )/multidrug resistance protein‐1 and rat M rp2/ B crp/ B sep also mediated the transport of the 20( S )‐protopanaxatriol‐type ginsenosides. Glomerular‐filtration‐based renal excretion of the 20( S )‐protopanaxatriol‐type ginsenosides was greater than that of the 20( S )‐protopanaxadiol‐type counterparts due to differences in plasma protein binding. Rifampin‐impaired hepatobiliary excretion of the 20( S )‐protopanaxatriol‐type ginsenosides was effectively compensated by the renal excretion in rats. The 20( S )‐protopanaxadiol‐type ginsenosides were potent inhibitors of OATP 1 B 3. Conclusion and Implications Differences in hepatobiliary and in renal excretory clearances caused markedly different systemic exposure and different elimination kinetics between the two types of ginsenosides. Caution should be exercised with the long‐circulating 20( S )‐protopanaxadiol‐type ginsenosides as they could induce hepatobiliary herb–drug interactions, particularly when patients receive long‐term therapies with high‐dose i.v. S anqi or ginseng extracts.