title: Cyclosporin A, tacrolimus and sirolimus are potent inhibitors of the human breast cancer resistance protein (ABCG2) and reverse resistance to mitoxantrone and topotecan.
abstract: OBJECTIVE
  Several studies have demonstrated significant interactions between immunosuppressants (e.g., cyclosporin A) and chemotherapeutic drugs that are BCRP substrates (e.g., irinotecan), resulting in increased bioavailability and reduced clearance of these agents. One possible mechanism underlying this observation is that the immunosuppressants modulate the pharmacokinetics of these drugs by inhibiting BCRP. Therefore, the aim of this study was to determine whether the immunosuppressants cyclosporin A, tacrolimus and sirolimus are inhibitors and/or substrates of BCRP.
  
  
  METHODS
  First, the effect of the immunosuppressants on BCRP efflux activity in BCRP-expressing HEK cells was measured by flow cytometry.
  
  
  RESULTS
  Cyclosporin A, tacrolimus and sirolimus significantly inhibited BCRP-mediated efflux of pheophorbide A, mitoxantrone and BODIPY-prazosin. The EC(50) values of cyclosporin A, tacrolimus and sirolimus for inhibition of BCRP-mediated pheophorbide A efflux were 4.3 +/- 1.9 microM, 3.6 +/- 1.8 microM and 1.9 +/- 0.4 microM, respectively. Cyclosporin A, tacrolimus and sirolimus also effectively reversed resistance of HEK cells to topotecan and mitoxantrone conferred by BCRP. When direct efflux of cyclosporin A, tacrolimus and sirolimus was measured, these compounds were found not to be transported by BCRP. Consistent with this finding, BCRP did not confer resistance to the immunosuppressants in HEK cells.
  
  
  CONCLUSIONS
  These results indicate that cyclosporin A, tacrolimus and sirolimus are effective inhibitors but not substrates of BCRP. These findings could explain the altered pharmacokinetics of BCRP substrate drugs when co-administered with the immunosuppressants and suggest that pharmacokinetic modulation by the immunosuppressants may improve the therapeutic outcome of these drugs.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, 98195-7610, USA.
authors.forename: Anshul
authors.initials: A
authors.lastname: Gupta
authors.forename: Yang
authors.initials: Y
authors.lastname: Dai
authors.forename: R Robert
authors.initials: RR
authors.lastname: Vethanayagam
authors.forename: Mary F
authors.initials: MF
authors.lastname: Hebert
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Thummel
authors.forename: Jashvant D
authors.initials: JD
authors.lastname: Unadkat
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Ross
authors.forename: Qingcheng
authors.initials: Q
authors.lastname: Mao
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008942:Mitoxantrone / Q000493:pharmacokinetics / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D020123:Sirolimus / Q000494:pharmacology; D013379:Substrate Specificity; D016559:Tacrolimus / Q000494:pharmacology; D019772:Topotecan / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D009363:Neoplasm Proteins; D019772:Topotecan; D016572:Cyclosporine; D008942:Mitoxantrone; D020123:Sirolimus; D016559:Tacrolimus