Molecular mechanisms governing different pharmacokinetics of ginsenosides and potential for ginsenoside-perpetrated herb-drug interactions on OATP1B3

Br J Pharmacol. 2015 Feb;172(4):1059-73. doi: 10.1111/bph.12971. Epub 2015 Jan 20.

Abstract

Background and purpose: Ginsenosides are bioactive saponins derived from Panax notoginseng roots (Sanqi) and ginseng. Here, the molecular mechanisms governing differential pharmacokinetics of 20(S)-protopanaxatriol-type ginsenoside Rg1 , ginsenoside Re and notoginsenoside R1 and 20(S)-protopanaxadiol-type ginsenosides Rb1, Rc and Rd 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 (Oatp)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 OATP1Bs.

Key results: All the ginsenosides were bound to human OATP1B3 and rat Oatp1b2 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 Mrp2/Bcrp/Bsep 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 OATP1B3.

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. Sanqi or ginseng extracts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Blood Proteins / metabolism
  • Female
  • Ginsenosides / pharmacokinetics*
  • HEK293 Cells
  • Herb-Drug Interactions*
  • Humans
  • Kidney / metabolism
  • Liver / metabolism
  • Liver-Specific Organic Anion Transporter 1
  • Male
  • Multidrug Resistance-Associated Proteins / metabolism
  • Neoplasm Proteins / metabolism
  • Organic Anion Transporters / genetics
  • Organic Anion Transporters, Sodium-Independent / genetics
  • Rats, Sprague-Dawley
  • Solute Carrier Organic Anion Transporter Family Member 1B3

Substances

  • ABCB1 protein, human
  • ABCB11 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Abcb11 protein, rat
  • Abcg2 protein, rat
  • Blood Proteins
  • Ginsenosides
  • Liver-Specific Organic Anion Transporter 1
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Organic Anion Transporters
  • Organic Anion Transporters, Sodium-Independent
  • SLCO1B1 protein, human
  • SLCO1B3 protein, human
  • Slco1b2 protein, rat
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • multidrug resistance-associated protein 2