Interactions of azole antifungal agents with the human breast cancer resistance protein (BCRP)

J Pharm Sci. 2007 Dec;96(12):3226-35. doi: 10.1002/jps.20963.


Breast cancer resistance protein (BCRP) is an efflux transporter that plays an important role in drug disposition. The goal of this study was to investigate the interactions of azole antifungal agents, ketoconazole, itraconazole, fluconazole, and voriconazole, with BCRP. First, the effect of the azoles on BCRP efflux activity in BCRP-overexpressing HEK cells was determined by measuring intracellular pheophorbide A (PhA) fluorescence using flow cytometry. We found that keotoconazole and itraconazole significantly inhibited BCRP-mediated efflux of PhA at low microM concentrations. However, fluconazole only mildly inhibited and voriconazole did not inhibit BCRP efflux activity at concentrations up to 100 microM. The IC(50) value of ketoconazole for inhibition of BCRP-mediated PhA efflux was 15.3 +/- 6.5 microM. Ketoconazole and itraconazole also effectively reversed BCRP-mediated resistance of HEK cells to topotecan. When direct efflux of [(3)H]ketoconazole was measured in BCRP-overexpressing HEK cells, we found that [(3)H]ketoconazole was not transported by BCRP. Consistent with this finding, BCRP did not confer resistance to ketoconazole and itraconazole in HEK cells. Taken together, ketoconazole and itraconazole are BCRP inhibitors, but fluconazole and voriconazole are not. These results suggest that BCRP could play a significant role in the pharmacokinetic interactions of ketoconazole or itraconazole with BCRP substrate drugs.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / antagonists & inhibitors*
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Antifungal Agents / metabolism
  • Antifungal Agents / pharmacology*
  • Antineoplastic Agents / pharmacology
  • Cell Line
  • Cell Survival / drug effects
  • Chlorophyll / analogs & derivatives
  • Chlorophyll / metabolism
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Drug Resistance, Neoplasm / drug effects
  • Flow Cytometry
  • Fluconazole / pharmacology
  • Fluorescent Dyes / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Itraconazole / metabolism
  • Itraconazole / pharmacology*
  • Ketoconazole / metabolism
  • Ketoconazole / pharmacology*
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Pyrimidines / pharmacology
  • Topotecan / pharmacology
  • Transfection
  • Triazoles / pharmacology
  • Voriconazole


  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antifungal Agents
  • Antineoplastic Agents
  • Fluorescent Dyes
  • Neoplasm Proteins
  • Pyrimidines
  • Triazoles
  • Chlorophyll
  • Itraconazole
  • Topotecan
  • Fluconazole
  • pheophorbide a
  • Voriconazole
  • Ketoconazole