PT - JOURNAL ARTICLE AU - Cindy Q. Xia AU - Ning Liu AU - Gerald T. Miwa AU - Liang-Shang Gan TI - Interactions of Cyclosporin A with Breast Cancer Resistance Protein AID - 10.1124/dmd.106.011866 DP - 2007 Apr 01 TA - Drug Metabolism and Disposition PG - 576--582 VI - 35 IP - 4 4099 - http://dmd.aspetjournals.org/content/35/4/576.short 4100 - http://dmd.aspetjournals.org/content/35/4/576.full SO - Drug Metab Dispos2007 Apr 01; 35 AB - 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). The American Society for Pharmacology and Experimental Therapeutics