BCRP transports dipyridamole and is inhibited by calcium channel blockers

Pharm Res. 2005 Dec;22(12):2023-34. doi: 10.1007/s11095-005-8384-4. Epub 2005 Nov 1.


Purpose: We investigated whether dipyridamole and various calcium channel blockers are inhibitors and/or substrates of breast cancer resistance protein (BCRP).

Methods: The effect of dipyridamole and the calcium channel blockers on mitoxantrone efflux by BCRP-overexpressing human embryonic kidney (HEK) cells was determined by flow cytometry. The ability of some of these compounds to reverse BCRP-mediated mitoxantrone resistance was measured by cytotoxicity assays. Transport studies were performed using radiolabeled compounds.

Results: Dipyridamole, nicardipine, nitrendipine, and nimodipine effectively inhibited BCRP-mediated mitoxantrone efflux; however, bepridil, diltiazem, and verapamil had no significant effect. Nifedipine is a much weaker BCRP inhibitor compared with other dihydropyridines tested. Nicardipine and dipyridamole were the most potent BCRP inhibitors among the compounds tested with IC50 values of 4.8 +/- 1.3 and 6.4 +/- 0.9 microM, respectively. Nicardipine and dipyridamole also effectively reversed BCRP-mediated mitoxantrone resistance in HEK cells. [3H]Nitrendipine was found not to be transported by BCRP. However, the transport of [3H]dipyridamole by BCRP was observed in both HEK and Madin-Darby canine kidney cells stably expressing the transporter, and this transport was completely abolished by fumitremorgin C, a known BCRP inhibitor.

Conclusions: Dipyridamole and several dihydropyridines are effective BCRP inhibitors, but bepridil, diltiazem, and verapamil are not. We also identified a new BCRP substrate, dipyridamole.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / antagonists & inhibitors*
  • ATP-Binding Cassette Transporters / metabolism*
  • Algorithms
  • Animals
  • Antineoplastic Agents / pharmacology
  • Biological Transport, Active
  • Calcium Channel Blockers / metabolism
  • Calcium Channel Blockers / pharmacology*
  • Cell Line
  • Cell Survival / drug effects
  • Dihydropyridines / metabolism
  • Dihydropyridines / pharmacology
  • Dipyridamole / metabolism*
  • Dogs
  • Electrophoresis, Polyacrylamide Gel
  • Flow Cytometry
  • Humans
  • Immunoblotting
  • Microscopy, Confocal
  • Mitoxantrone / pharmacology
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / metabolism*
  • Nitrendipine / metabolism
  • Platelet Aggregation Inhibitors / metabolism*
  • Rats
  • Rats, Sprague-Dawley


  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Calcium Channel Blockers
  • Dihydropyridines
  • Neoplasm Proteins
  • Platelet Aggregation Inhibitors
  • Dipyridamole
  • Nitrendipine
  • Mitoxantrone