Cyclosporin A, tacrolimus and sirolimus are potent inhibitors of the human breast cancer resistance protein (ABCG2) and reverse resistance to mitoxantrone and topotecan

• Published in: Cancer chemotherapy and pharmacology Vol. 58; no. 3; pp. 374 - 383
• Main Authors: GUPTA, Anshul, YANG DAI, VETHANAYAGAM, R. Robert, HEBERT, Mary F, THUMMEL, Kenneth E, UNADKAT, Jashvant D, ROSS, Douglas D, QINGCHENG MAO
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.09.2006; Springer Nature B.V
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - biosynthesis; Biological and medical sciences; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Survival - drug effects; Cyclosporine - pharmacology; Drug Resistance, Neoplasm - drug effects; Female; Flow Cytometry; Humans; Immunosuppressive Agents - pharmacology; Medical sciences; Mitoxantrone - pharmacokinetics; Mitoxantrone - pharmacology; Neoplasm Proteins - biosynthesis; Pharmacology. Drug treatments; Sirolimus - pharmacology; Substrate Specificity; Tacrolimus - pharmacology; Topotecan - pharmacokinetics; Topotecan - pharmacology; Antineoplastic agent; Sirolimus; Cyclosporin A; Breast cancer resistance protein; Macrocycle; ABCG2 gene; Isomerases; Ciclosporin; Protein synthesis inhibitor; Mitoxantrone; Human; BCRP; Treatment resistance; Anthraquinone derivatives; Enzyme; DNA topoisomerase; Enzyme inhibitor; Lactone; Topotecan; Macrolide; Alkylating agent; Antimetabolic; Tacrolimus; Reversibility; Inhibitor; Immunosuppressive agent; ABC transporter
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-005-0173-6

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. First, the effect of the immunosuppressants on BCRP efflux activity in BCRP-expressing HEK cells was measured by flow cytometry. 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. 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.