Regular Article
Competitive Inhibition of Human Organic Anion Transporters 1 (SLC22A6), 3 (SLC22A8) and 4 (SLC22A11) by Major Components of the Medicinal Herb Salvia miltiorrhiza (Danshen)

https://doi.org/10.2133/dmpk.DMPK-12-RG-116Get rights and content

Summary:

When herbal products are used in combination therapy with drugs, alterations in pharmacokinetics, pharmacodynamics, and toxicity can result. Many active components of herbal products are organic anions, and human organic anion transporter 1 (hOAT1, SLC22A6), hOAT3 (SLC22A8), and hOAT4 (SLC22A11) have been identified as potential sites of drug-drug interactions. Therefore, we assessed the effects of lithospermic acid (LSA), rosmarinic acid (RMA), salvianolic acid A (SAA), salvianolic acid B (SAB), and tanshinol (TSL), components of the herbal medicine Danshen, on the function of these transporters. Kinetic analysis demonstrated a competitive mechanism of inhibition for all five. Ki values (μΜ) were estimated as 20.8 ± 2.1 (LSA), 0.35 ± 0.06 (RMA), 5.6 ± 0.3 (SAA), 22.2 ± 1.9 (SAB), and 40.4 ± 12.9 (TSL) on hOAT1 and as 0.59 ± 0.26 (LSA), 0.55 ± 0.25 (RMA), 0.16 ± 0.03 (SAA), 19.8 ± 8.4 (SAB), and 8.6 ± 3.3 (TSL) on hOAT3. No significant inhibition of hOAT4 activity by TSL was observed. Using published human pharmacokinetic values, unbound Cmax/Ki ratios were calculated as an indicator of in vivo drug-drug interaction potential. Analysis indicated a strong interaction potential for RMA and TSL on both hOAT1 and hOAT3 and for LSA on hOAT3. Thus, herb-drug interactions may occur in vivo in situations of co-administration of Danshen and clinical therapeutics known to be hOAT1/hOAT3 substrates.

References (44)

  • C.C. Wong et al.

    Flavonoid conjugates interact with organic anion transporters (OATs) and attenuate cytotoxicity of adefovir mediated by organic anion transporter 1 (OAT1/SLC22A6)

    Biochem. Pharmacol.

    (2011)
  • N. Bakhiya et al.

    Molecular evidence for an involvement of organic anion transporters (OATs) in aristolochic acid nephropathy

    Toxicology

    (2009)
  • H. Ueo et al.

    Human organic anion transporter hOAT3 is a potent transporter of cephalosporin antibiotics, in comparison with hOAT1

    Biochem. Pharmacol.

    (2005)
  • Y. Uwai et al.

    Inhibitory effect of caffeic acid on human organic anion transporters hOAT1 and hOAT3: a novel candidate for food-drug interaction

    Drug Metab. Pharmacokinet.

    (2011)
  • L. Zhou et al.

    Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use

    J. Clin. Pharmacol.

    (2005)
  • R.W. Jiang et al.

    Chemistry and biological activities of caffeic acid derivatives from Salvia miltiorrhiza

    Curr. Med. Chem.

    (2005)
  • C.L. Liu et al.

    Salvianolic acid B inhibits hydrogen peroxide-induced endothelial cell apoptosis through regulating PI3K/Akt signaling

    PLoS ONE

    (2007)
  • D. Yuan et al.

    Quantitative analysis of the marker compounds in Salvia miltiorrihiza root and its phytomedicinal preparations

    Chem. Pharm. Bull. (Tokyo)

    (2005)
  • T. Lu et al.

    Plasma and urinary tanshinol from Salvia miltiorrhiza (Danshen) can be used as pharmacokinetic markers for cardiotonic pills, a cardiovascular herbal medicine

    Drug Metab. Dispos.

    (2008)
  • D.H. Sweet et al.

    The organic anion transporter family: from physiology to ontogeny and the clinic

    Am. J. Physiol. Renal Physiol.

    (2001)
  • A.L. VanWert et al.

    Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

    Biopharm. Drug Dispos.

    (2010)
  • U. Jaehde et al.

    Effect of probenecid on the distribution and elimination of ciprofloxacin in humans

    Clin. Pharmacol. Ther.

    (1995)
  • Cited by (0)

    View full text