Transport of diclofenac by breast cancer resistance protein (ABCG2) and stimulation of multidrug resistance protein 2 (ABCC2)-mediated drug transport by diclofenac and benzbromarone,” Drug Metabolism and Disposition

ABSTRACT: Diclofenac is an important analgesic and anti-inflammatory drug, widely used for treatment of postoperative pain, rheumatoid arthritis, and chronic pain associated with cancer. Consequently, diclofenac is often used in combination regimens and undesirable drug-drug interactions may occur. Because many drug-drug interactions may occur at the level of drug transporting proteins, we studied interactions of diclofenac with apical ATP-binding cassette (ABC) multidrug efflux transporters. Using Madin-Darby canine kidney (MDCK)-II cells transfected with human P-glycoprotein (P-gp; MDR1/ABCB1), multidrug resistance protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2) and murine Bcrp1, we found that diclofenac was efficiently transported by murine Bcrp1 and moderately by human BCRP but not by P-gp or MRP2. Furthermore, in Sf9-BCRP membrane vesicles diclofenac inhibited transport of methotrexate in a concentration-dependent manner. We next used MDCK-II-MRP2 cells to study interactions of diclofenac with MRP2-mediated drug transport. Diclofenac stimulated paclitaxel, docetaxel, and saquinavir transport at only 50 M. We further found that the uricosuric drug benzbromarone stimulated MRP2 at an even lower concentration, having maximal stimulatory activity at only 2 M. Diclofenac and benzbromarone stimulated MRP2-mediated transport of amphipathic lipophilic drugs at 10-and 250-fold lower concentrations, respectively, than reported for other MRP2 stimulators. Because these concentrations are readily achieved in patients, adverse drug-drug interactions may occur, for example, during cancer therapy, in which drug concentrations are often critical and stimulation of elimination via MRP2 may result in suboptimal chemotherapeutic drug concentrations. Moreover, stimulation of MRP2 activity in tumors may lead to increased efflux of chemotherapeutic drugs and thereby drug resistance. Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits potent analgesic and anti-inflammatory properties and is extensively used to treat postoperative pain, rheumatoid arthritis, osteoarthritis, and acute gouty arthritis Because it is recognized more and more that many interactions of drugs occur at the level of drug-transporting proteins, we investigated whether diclofenac is a substrate of one of the apical ABC transporters, using MDCK-II cells transfected with human P-gp, MRP2, BCRP, or murine Bcrp1 cDNA. We further used the MDCK-II cells transduced with human and mouse MRP2/Mrp2 to examine whether diclofenac could modulate MRP2-mediated transport of taxane anticancer drugs. To date, several compounds, e.g., probenecid, sulfinpyrazone, and sulfanitran, have been shown to stimulate the MRP2-mediated transport of lipophilic amphipathic drugs (Huisman et al., Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.108.023200. ABBREVIATIONS: NSAID, nonsteroidal anti-inflammatory drug; MTX, methotrexate; ABC, ATP-binding cassette; MRP, multidrug resistance protein; MDCK, Madin-Darby canine kidney; P-gp, P-glycoprotein; BCRP, breast cancer resistance protein; GF120918, N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide; Ko143, 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12␣-octahydropyrazino[1Ј,2Ј:1,6]pryrido[3,4-b]indol-3-yl)-propionic acid tert-butyl ester; E 2 17␤G, estradiol-17␤-glucuronide