Application and limitation of inhibitors in drug-transporter interactions studies

Int J Pharm. 2008 May 22;356(1-2):12-8. doi: 10.1016/j.ijpharm.2007.12.024. Epub 2007 Dec 24.


The objective of the present study was to investigate the reliability of transporter inhibitors in the elucidation of drug-transporter interactions when multiple transporters are present in a test system. The bidirectional permeabilities of digoxin, estrone-3-sulfate (E3S), and sulfasalazine, substrates of P-gp, BCRP/MRP2 and unspecified efflux transporters, respectively, were examined in Caco-2 and MDR-MDCK cells in the absence and presence of transporter inhibitors: CsA (P-gp), FTC (BCRP) and MK571 (MRP). Digoxin showed significant efflux ratios (ER) in both Caco-2 (ER=17) and MDR-MDCK (ER=120), whereas E3S and sulfasalazine only showed significant efflux in Caco-2 (ER=15 and 88, respectively) but not in MDR-MDCK cells (ER=1.1 and 1.3, respectively). CsA at 10 microM showed complete inhibition of digoxin efflux, partial inhibition of E3S efflux and no effect on sulfasalazine efflux. FTC and MK571 had different inhibitory effects on the efflux of these compounds. The present study shows evidence of the functional expression of multiple efflux transporter systems in Caco-2 cells. Although the use of Caco-2 cells and selected inhibitors of efflux transporters can provide useful mechanistic information on drug-drug interactions involving efflux transporters, the potential cross-reaction of inhibitors with multiple transporters makes it difficult to discern the role of individual transporters in drug transport or drug-drug interactions.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / drug effects*
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / drug effects*
  • Animals
  • Biological Transport / drug effects
  • Caco-2 Cells
  • Cell Line
  • Cyclosporine / pharmacology
  • Digoxin / pharmacokinetics
  • Dogs
  • Drug Interactions
  • Estrone / analogs & derivatives
  • Estrone / pharmacokinetics
  • Humans
  • Indoles / pharmacology
  • Kidney / cytology
  • Kidney / drug effects
  • Kidney / metabolism
  • Multidrug Resistance-Associated Proteins / drug effects*
  • Neoplasm Proteins / drug effects*
  • Permeability / drug effects
  • Propionates / pharmacology
  • Quinolines / pharmacology
  • Sulfasalazine / pharmacokinetics


  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Indoles
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Propionates
  • Quinolines
  • Estrone
  • Sulfasalazine
  • verlukast
  • Digoxin
  • Cyclosporine
  • tryptoquivaline
  • estrone sulfate