Transport of Diclofenac by Breast Cancer Resistance Protein (ABCG2) and Stimulation of Multidrug Resistance Protein 2 (ABCC2)-Mediated Drug Transport by Diclofenac and Benzbromarone

Abstract

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 (Davies and Anderson, 1997). Diclofenac is also widely used to treat pain associated with cancer, and treatment combinations of diclofenac with chemotherapeutic drugs are common. In addition, preclinical evidence is accumulating that NSAIDs, including diclofenac, have beneficial effects as adjuvant therapy in treatment of some types of cancer (Crokart et al., 2005;Johnsen et al., 2005). Due to this widespread co-use of drugs, interactions of NSAIDs with chemotherapeutic drugs can result in unexpected toxicities or failure of chemotherapy. For example, NSAIDs are known to restrict plasma clearance of methotrexate (MTX). When MTX is used at high-dose regimens for cancer treatment, interactions with NSAIDs can result in severe toxicity, with sometimes fatal outcome (Thyss et al., 1986). In a recent study, using human kidney slides, it was demonstrated that diclofenac and its acyl-glucuronide c...

Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac

“…Similar to rats, canalicular DCF-AG excretion would likely have been mediated by Mrp2 given the 88% protein sequence homology between mouse and rat Mrp2 (Altschul et al, 2005). Another canalicular transporter, breast cancer resistance protein (Bcrp/Abcg2), has been also demonstrated to transport DCF (Lagas et al, 2009). However, exploratory studies in our laboratory with Bcrp-KO mice resulted in equivalent DCF-AG biliary excretion compared with WT (data not shown).…”

Involvement of the Pleiotropic Drug Resistance Response, Protein Kinase C Signaling, and Altered Zinc Homeostasis in Resistance of Saccharomyces cerevisiae to Diclofenac

“…This may be due either to direct transport of diclofenac by Pdr5p or to secondary effects of Pdr5p deletion or overexpression (40). Interestingly, a murine homolog of Pdr5p, BCRP1 (ABCG2), can efficiently transport diclofenac in vitro (24). Previously, Mima et al (34) found that overexpression of the polyamine transporter encoded by TPO1 decreases sensitivity to diclofenac in yeast.…”

Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects

“…Several drugs have been identified as substrates and/or inhibitors of BCRP by means of in vitro studies. Substrates include antivirals [e.g., acyclovir (Jonker et al, 2005)], statins [e.g., pravastatin (Matsushima et al, 2005) and rosuvastatin (Huang et al, 2006)], anticancer drugs [e.g., topotecan (Maliepaard et al, 1999)], antibiotics [e.g., ciprofloxacin and ofloxacin (Ando et al, 2007)], as well as diclofenac (Lagas et al, 2009), sulfasalazine (van der Heijden et al, 2004, and cimetidine (Jonker et al, 2005). Furthermore, endogenous substances and metabolites such as vitamin K 3 (Shukla et al, 2007), estrone-3-sulfate, dehydroepiandrosterone sulfate (Suzuki et al, 2003), and uric acid (Woodward et al, 2009) have been shown to be transported by BCRP.…”