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

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Received for publication July 6, 2006.
Revised January 8, 2007.
Accepted for publication January 9, 2007.

Interactions of Cyclosporin A with Breast Cancer Resistance Protein

Cindy Qing Xia 1*, Ning Liu 1, Gerald T Miwa 1, Lawrence L. Gan 2

1 Millennium Pharmaceuticals, Inc. 2 Boehringer-Ingelheim Pharmaceuticals, Inc.

* Address correspondence to: E-mail: xia{at}mpi.com

Abstract

The objective of this study was to investigate if cyclosporin A (CsA) is a modulator for 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 (31388 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]-E3S and [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 as a BCRP substrate, respectively. The inhibitory potency of CsA on BCRP wild type or its R482T mutant was lower than that on P-gp. 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 to 400 ng/mL) (Emilia et al., 1998).


Key words: ABC transporters, drug efflux, drug-drug interactions


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