Interaction of Nonsteroidal Anti-Inflammatory Drugs with Multidrug Resistance Protein (MRP) 2/ABCC2- and MRP4/ABCC4-Mediated Methotrexate Transport

El-Sheikh, Azza A. K.; Heuvel, Jeroen J. M. W. van den; Koenderink, Jan B.; Rüssel, Frans G. M.

doi:10.1124/jpet.106.110379

Cited by 204 publications

(159 citation statements)

References 25 publications

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“…Little is known about the effect of P-glycoprotein or MRP1 modulators on MRP2 and/or MRP4, and further, few (if any) inhibitors specific for the latter transporters have been identified. However, MRP2 and MRP4 transport can be modulated by an array of organic anions, some of which are therapeutically useful agents (Bakos et al, 2000;de Wolf et al, 2007;El-Sheikh et al, 2007). Given the contributions of MRP2 and MRP4 to the pharmacokinetic profiles of numerous therapeutic agents (and hence their efficacy and/or safety) (Russel et al, 2008;Lagas et al, 2009), such information is clinically relevant.…”

Section: Introductionmentioning

confidence: 99%

Chalcogenopyrylium Dyes as Differential Modulators of Organic Anion Transport by Multidrug Resistance Protein 1 (MRP1), MRP2, and MRP4

et al. 2013

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Multidrug resistance proteins (MRPs) mediate the ATP-dependent efflux of structurally diverse compounds, including anticancer drugs and physiologic organic anions. Five classes of chalcogenopyrylium dyes (CGPs) were examined for their ability to modulate transport of [ 3 H]estradiol glucuronide (E 2 17bG; a prototypical MRP substrate) into MRP-enriched inside-out membrane vesicles.Additionally, some CGPs were tested in intact transfected cells using a calcein efflux assay. Sixteen of 34 CGPs inhibited MRP1-mediated E 2 17bG uptake by >50% (IC 50 values: 0.7-7.6 mM). Of 9 CGPs with IC 50 values £2 mM, two belonged to class I, two to class III, and five to class V. When tested in the intact cells, only 4 of 16 CGPs (at 10 mM) inhibited MRP1-mediated calcein efflux by >50% (III-1, V-3, V-4, V-6), whereas a fifth (I-5) inhibited efflux by just 23%.These five CGPs also inhibited [ 3 H]E 2 17bG uptake by MRP4. In contrast, their effects on MRP2 varied, with two (V-4, V-6) inhibiting E 2 17bG transport (IC 50 values: 2.0 and 9.2 mM) and two (V-3, III-1) stimulating transport (>2-fold), whereas CGP I-5 had no effect. Strikingly, although V-3 and V-4 had opposite effects on MRP2 activity, they are structurally identical except for their chalcogen atom (Se versus Te). This study is the first to identify class V CGPs, with their distinctive methine or trimethine linkage between two disubstituted pyrylium moieties, as a particularly potent class of MRP modulators, and to show that, within this core structure, differences in the electronegativity associated with a chalcogen atom can be the sole determinant of whether a compound will stimulate or inhibit MRP2.

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Section: Introductionmentioning

confidence: 99%

Chalcogenopyrylium Dyes as Differential Modulators of Organic Anion Transport by Multidrug Resistance Protein 1 (MRP1), MRP2, and MRP4

et al. 2013

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“…Several experimental models have been developed to investigate the hepatobiliary transporters, their distributions, and functions. These experimental models include liver canalicular membrane vesicles (El-Sheikh et al, 2007), isolated and cultured hepatocytes (Li et al, 1999), isolated perfused liver (Zamek-Gliszczynski et al, 2006), and transporter-deficient animal models (Kuroda et al, 2004). However, these models have limited utility in providing information on biliary excretion, as they are not optimal to obtain quantitative information (membrane vesicles and cultured hepatocytes) or require complicated and labor intensive experiments.…”

Section: Introductionmentioning

confidence: 99%

Assessment of the Roles of P-glycoprotein and Cytochrome P450 in Triptolide-induced Liver Toxicity in Sandwich-Cultured Rat Hepatocyte Model

et al. 2013

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Triptolide (TP), a main bioactive component of Tripterygium wilfordii Hook F., is a promising agent for treatment of autoimmune diseases. However, a high incidence of dose-limiting hepatotoxicity was observed in the clinic. Sandwich-cultured rat hepatocyte model was used in this study to identify the involvement of P-glycoprotein (P-gp) in TP disposition and to evaluate TP-induced hepatotoxicity after modulation of P-gp by the known inhibitors, ritonavir and tariquidar, and known inducers, phenobarbital, quercetin, and H 2 O 2 . Our data showed that biliary clearance of TP reduced 73.7% and 84.2% upon treatment of ritonavir (25 mM) and tariquidar (5 mM), respectively. In contrast, increases of 346%, 280%, and 273% in biliary clearance of TP were observed with treatment of phenobarbital (1.0 mM), quercetin (20 mM), and H 2 O 2 (0.5 mM), respectively. The TP-induced hepatotoxicity increased by twofold when CYP activity was blocked by 1-aminobenzotriazole, suggesting that CYP and P-gp may both contribute to the detoxification of TP in the SCRH model. In addition, hepatotoxicity and the expression of apoptosis proteins Bax and Bcl-2 were correlated qualitatively with the TP exposure duration and its intracellular concentration, which, in turn, can be modulated by P-gp inhibitors or inducers. Our results for the first time demonstrated that in addition to CYP-mediated metabolism, P-gp also plays an important role in the disposition of TP and TP-induced hepatotoxicity. Thus, the modulation of canalicular P-gp has a potential to cause drug-drug interaction between TP and the coadministered P-gp inhibitors or inducers in the clinic.

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“…29,30) Also, NSAIDs such as salicylate, piroxicam, ibuprofen, naproxen, sulindac, tolmetin, etodolac, dicrofenac, indomethacin, ketoprofen, phenylbutazone and celecoxib inhibit MRP1, MRP2 and/or MRP4. 30,31) MRP2 and MRP3 share 48% homology at the amino acid level, 32) and have several common inhibitors. 33) Thus, it is not unexpected that uricosuric drugs and NSAIDs also inhibit Mrp3 (Figs.…”

Section: Discussionmentioning

confidence: 99%

Screening to Identify Multidrug Resistance-Associated Protein Inhibitors with Neuroblastoma-Selective Cytotoxicity

Nakamichi

Ishimoto

Yamauchi

et al. 2016

Biological & Pharmaceutical Bulletin

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The aim of the present study is to discover multidrug resistance-associated protein (MRP) inhibitors with neuroblastoma-selective cytotoxicity by means of fluorescence assay with a membrane-permeable fluorescent dye, Fluo-8 AM, based on our observation that gene expression of Mrp3 in neuroblastoma Neuro2a cells was remarkably higher than that in primary cultured cortical neurons, as determined by real-time PCR. Neuro2a cells showed minimal fluorescence upon incubation with Fluo-8 AM. However, blocking of Mrp3 efflux function by small interfering RNA (siRNA) transfection or inhibition with probenecid resulted in significant dye accumulation, observed as an increase of fluorescence. Interestingly, Mrp3 siRNA or probenecid treatment also resulted in increased cytotoxicity, as evidenced by decreased 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-reducing activity of Neuro2a, with a concomitant increase in release of lactate dehydrogenase. On the other hand, primary cultured neurons exhibited higher fluorescence intensity after incubation with Fluo-8 AM regardless of addition of probenecid. Also, probenecid only minimally affected MTT-reducing activity. Thus, probenecid showed selective cytotoxicity towards Neuro2a cells. Based on these findings, we screened a series of established therapeutic agents for ability to induce Fluo-8 accumulation in Neuro2a cells. Several uricosuric and nonsteroidal anti-inflammatory drugs were identified, and these drugs were confirmed to decrease MTT-reducing activity selectively in Neuro2a. There was a negative linear correlation between Fluo-8 accumulation and cytotoxicity of these agents. Although the compounds identified here are insufficiently potent for practical application, further screening to discover higher-affinity MRP3 inhibitors using larger chemical libraries may uncover drug candidates with potent neuroblastoma-selective cytotoxicity.

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Interaction of Nonsteroidal Anti-Inflammatory Drugs with Multidrug Resistance Protein (MRP) 2/ABCC2- and MRP4/ABCC4-Mediated Methotrexate Transport

Cited by 204 publications

References 25 publications

Chalcogenopyrylium Dyes as Differential Modulators of Organic Anion Transport by Multidrug Resistance Protein 1 (MRP1), MRP2, and MRP4

Chalcogenopyrylium Dyes as Differential Modulators of Organic Anion Transport by Multidrug Resistance Protein 1 (MRP1), MRP2, and MRP4

Assessment of the Roles of P-glycoprotein and Cytochrome P450 in Triptolide-induced Liver Toxicity in Sandwich-Cultured Rat Hepatocyte Model

Screening to Identify Multidrug Resistance-Associated Protein Inhibitors with Neuroblastoma-Selective Cytotoxicity

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