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Drug Metabolism and Disposition Fast Forward
First published on January 12, 2007; DOI: 10.1124/dmd.106.011866

0090-9556/07/3504-576-582$20.00
DMD 35:576-582, 2007

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Interactions of Cyclosporin A with Breast Cancer Resistance Protein

Cindy Q. Xia, Ning Liu, Gerald T. Miwa, and Liang-Shang Gan

Drug Metabolism and Pharmacokinetics, Drug Safety and Disposition, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts

The objective of this study was to investigate whether cyclosporin A (CsA) is a modulator for breast cancer resistance protein (BCRP). The interactions between CsA and BCRP were evaluated by using both membrane- and cell-based assays. CsA inhibited BCRP or BCRP R482T mutant-associated ATPase with an IC50 of 26.1 and 7.3 µM (31,388 and 8779 ng/ml), respectively, indicating that CsA is a modulator for BCRP and its R482T mutant. The apparent permeability (Papp) of CsA was not affected by the BCRP-specific inhibitor Ko143 in both apical-to-basolateral (A-to-B) and basolateral-to-apical (B-to-A) directions in hBCRP- or mBcrp-transfected MDCKII cells, whereas CsA at 50 µM significantly increased the A-to-B transport and decreased B-to-A transport of BCRP substrates, [3H]estrone-3-sulfate ([3H]E3S) and [3H]methotrexate ([3H]MTX), in hBCRP- and mBcrp1-trasfected MDCKII cells. Similar to cellular transport studies, CsA did not exhibit ATP-dependent uptake in BCRP-expressed membrane vesicles but inhibited the ATP-mediated E3S and MTX uptake in the same vesicles. The inhibitory constant (Ki) of CsA toward BCRP was 6.7 µM (8507 ng/ml) and 7.8 µM (9380 ng/ml) when using E3S or MTX, respectively, as a BCRP substrate. The inhibitory potency of CsA on BCRP wild type or its R482T mutant was lower than that on P-glycoprotein. The present studies demonstrate that CsA is an inhibitor but not a substrate for BCRP, and has low potential to cause drug-drug interactions with BCRP substrate drugs due to its weak inhibitory effect on BCRP and BCRP R482T mutant at its normal therapeutic blood concentrations (200–400 ng/ml) (Blood 91:362–363, 1998).

Address correspondence to: Dr. Cindy Q. Xia, Department of Drug Metabolism and Pharmacokinetics, Drug Safety and Disposition, Millennium Pharmaceuticals, Inc., 40 Landsdowne St., Cambridge, MA 02139. E-mail: xia{at}mpi.com




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