Competitive inhibition of human organic anion transporters 1 (SLC22A6), 3 (SLC22A8) and 4 (SLC22A11) by major components of the medicinal herb Salvia miltiorrhiza (Danshen)

Drug Metab Pharmacokinet. 2013;28(3):220-8. doi: 10.2133/dmpk.dmpk-12-rg-116. Epub 2012 Dec 11.

Abstract

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. K(i) values (µM) 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 C(max)/K(i) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzofurans / pharmacology
  • CHO Cells
  • Caffeic Acids / pharmacology
  • Cinnamates / pharmacology
  • Cricetulus
  • Depsides / pharmacology
  • Drugs, Chinese Herbal / pharmacology*
  • HEK293 Cells
  • Herb-Drug Interactions*
  • Humans
  • Lactates / pharmacology
  • Organic Anion Transport Protein 1 / antagonists & inhibitors*
  • Organic Anion Transporters, Sodium-Independent / antagonists & inhibitors*
  • Phenanthrolines / pharmacology*
  • Rosmarinic Acid
  • Salvia miltiorrhiza / chemistry*

Substances

  • Benzofurans
  • Caffeic Acids
  • Cinnamates
  • Depsides
  • Drugs, Chinese Herbal
  • Lactates
  • Organic Anion Transport Protein 1
  • Organic Anion Transporters, Sodium-Independent
  • Phenanthrolines
  • SLC22A11 protein, human
  • organic anion transport protein 3
  • tanshinol
  • lithospermic acid
  • dan-shen root extract
  • salvianolic acid A
  • salvianolic acid B