Evaluation of the interaction between nonsteroidal anti-inflammatory drugs and methotrexate using human organic anion transporter 3-transfected cells

Maeda, Akimitsu; Tsuruoka, Shuichi; Kanai, Yoshikatsu; Endou, Hitoshi; Saito, Kazuyuki; Miyamoto, Etsuko; Fujimura, Akio

doi:10.1016/j.ejphar.2008.08.023

Cited by 66 publications

(42 citation statements)

References 40 publications

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“…Thus, xenobiotic inhibition of Oat3 may prevent the renal toxicity of some b-lactams; however, inhibition may also limit the concentration of particular b-lactams in renal and postrenal infections, reducing efficacy. Importantly, it is now clear that many b-lactams may increase systemic exposure to competing substrates such as statin drugs (Windass et al, 2007) and methotrexate (Maeda et al, 2008) via interaction on Oat3. Furthermore, these findings indicate that Oat3 may be a major factor limiting brain exposure to b-lactams.…”

Section: Resultsmentioning

confidence: 99%

Organic Anion Transporter 3 Interacts Selectively with Lipophilicβ-Lactam Antibiotics

et al. 2013

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Transporters are major determinants of the disposition of xenobiotics and endogenous chemicals in the body. Organic anion transporter 3 (Oat3) functions in the kidney and brain to remove metabolic waste, toxins, and drugs, and thus transports diverse chemicals. Some b-lactam antibiotics interact with Oat3, and penicillin G exhibits a strong dependence on Oat3 for renal elimination. However, over 80 b-lactams exist, and many have not been assessed for an interaction with Oat3. Moreover, b-lactams continue to receive U.S. Food and Drug Administration approval. This study identified new b-lactam-Oat3 interactions, provided a head-to-head comparison with Oat1, and characterized the physicochemical determinants of affinity for Oat3. Cells expressing mouse Oat3 (mOat3) and Oat1 (mOat1), and human OAT3 (hOAT3) were used to test inhibitors, and high-performance liquid chromatography (HPLC) was used to measure transport. Of 26 b-lactams tested, 12 were clear inhibitors of Oat3, and 14 exhibited poor interactions. Inhibitors exhibited a nearly identical rank-order of potency against mOat3 and hOAT3. Oat1 demonstrated a poor interaction with most b-lactams. The majority of Oat3 inhibitors were substrates, and there were clear physicochemical differences between inhibitors and noninhibitors. That is, inhibitors had nearly 40% fewer hydrogen bond donors (P < 0.001), a lower total polar surface area (P < 0.05), and greater lipophilicity (LogP of inhibitors, +1.41; noninhibitors, 21.54; P < 0.001). Pharmacophore mapping revealed a prohibitive hydrogen bond donor group in noninhibitors adjacent to a hydrophobic moiety that was important for binding to Oat3. These findings indicate that Oat3 recognizes lipophilic b-lactams more readily. Moreover, this study has potential implications for designing b-lactams to avoid renal accumulation or brain efflux via Oat3.

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Section: Resultsmentioning

confidence: 99%

Organic Anion Transporter 3 Interacts Selectively with Lipophilicβ-Lactam Antibiotics

et al. 2013

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“…Methotrexate is taken up from the blood via OATs. NSAIDs can inhibit OATs, and when methotrexate and NSAIDs are used together, methotrexate toxicity can occur, manifesting as severe bone marrow suppression (76,77). DDIs at the level of P-glycoprotein (MDR1/ABCB1) in the proximal tubule and elsewhere are thought to explain the well known digoxin-quinidine interaction resulting in digoxin toxicity, including arrhythmias (78).…”

Section: Ddis and Drug-metabolite Interactionsmentioning

confidence: 99%

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Nigám¹,

Wu²,

Bush³

et al. 2015

Clinical Journal of the American Society of Nephrology

229

192

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The proximal tubule of the kidney plays a crucial role in the renal handling of drugs (e.g., diuretics), uremic toxins (e.g., indoxyl sulfate), environmental toxins (e.g., mercury, aristolochic acid), metabolites (e.g., uric acid), dietary compounds, and signaling molecules. This process is dependent on many multispecific transporters of the solute carrier (SLC) superfamily, including organic anion transporter (OAT) and organic cation transporter (OCT) subfamilies, and the ATP-binding cassette (ABC) superfamily. We review the basic physiology of these SLC and ABC transporters, many of which are often called drug transporters. With an emphasis on OAT1 (SLC22A6), the closely related OAT3 (SLC22A8), and OCT2 (SLC22A2), we explore the implications of recent in vitro, in vivo, and clinical data pertinent to the kidney. The analysis of murine knockouts has revealed a key role for these transporters in the renal handling not only of drugs and toxins but also of gut microbiome products, as well as liverderived phase 1 and phase 2 metabolites, including putative uremic toxins (among other molecules of metabolic and clinical importance). Functional activity of these transporters (and polymorphisms affecting it) plays a key role in drug handling and nephrotoxicity. These transporters may also play a role in remote sensing and signaling, as part of a versatile small molecule communication network operative throughout the body in normal and diseased states, such as AKI and CKD.

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“…MTX is taken up from blood across the basolateral membrane via organic anion transporters (OATs, SLC22A) 1 and 3 and reduced folate carrier-1 (Sekine et al, 1997;Hosoyamada et al, 1999;Cha et al, 2001;Nozaki et al, 2004), with subsequent excretion across the apical membrane via ATP-dependent efflux pumps, multidrug resistance proteins (MRPs, ABCC) 2 and 4 (Masuda et al, 1997;Chen et al, 2002;van Aubel et al, 2002) and breast cancer-resistant protein (BCRP) Nozaki et al, 2007) into urine. Thus, the competition of renal tubular secretion between MTX and NSAIDs has been thought to be a major cause of the drug interaction (Frenia and Long, 1992;Maeda et al, 2008). With respect to the inhibitory effect of NSAIDs on MTX uptake at the basolateral membrane, many reports have shown that several NSAIDs inhibit the transport of MTX via OAT1 and OAT3 (Uwai et al, 2000;Khamdang et al,2002;Takeda et al, 2002;Nozaki et al, 2004;Maeda et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Inhibition of Methotrexate Excretion by Glucuronides of Nonsteroidal Anti-inflammatory Drugs via Multidrug Resistance Proteins 2 and 4

Kawase

Yamamoto

Egashira

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Combined administration of methotrexate (MTX) and nonsteroidal anti-inflammatory drugs (NSAIDs) can result in a decreased systemic clearance of MTX. To date, inhibition of renal uptake via organic anion transporters and efflux via multidrug resistance-associated protein (MRPs) by NSAIDs has been recognized as possible sites of drug interaction between MTX and NSAIDs. Although most NSAIDs are glucuronidated in kidney tissue and excreted mainly as glucuronide conjugates, it is not fully known whether the glucuronides of NSAIDs (NSAIDs-Glu) inhibit MTX excretion via MRP2 and MRP4. The purpose of this study was to investigate the inhibitory effects of the glucuronides of several NSAIDs (diclofenac, R-and S-ibuprofen, R-and S-flurbiprofen, and R-and S-naproxen), as well as the parent NSAIDs on MTX uptake using human MRP2-and MRP4-expressing inside-out vesicles. Results confirm that all NSAIDs and NSAIDs-Glu examined exhibited stereoselective and concentrationdependent inhibitory effects on MTX uptake via MRP2 and MRP4. Notably, NSAIDs-Glu potently inhibited MTX uptake via MRP2 and MRP4 compared with the corresponding parent NSAIDs except for naproxen in MRP2 and S-flurbiprofen in MRP4. The present results support that the glucuronides of NSAIDs, as well as the parent NSAIDs, are involved in the inhibition of urinary excretion of MTX via MRP2 and MRP4.

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Evaluation of the interaction between nonsteroidal anti-inflammatory drugs and methotrexate using human organic anion transporter 3-transfected cells

Cited by 66 publications

References 40 publications

Organic Anion Transporter 3 Interacts Selectively with Lipophilicβ-Lactam Antibiotics

Organic Anion Transporter 3 Interacts Selectively with Lipophilicβ-Lactam Antibiotics

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Stereoselective Inhibition of Methotrexate Excretion by Glucuronides of Nonsteroidal Anti-inflammatory Drugs via Multidrug Resistance Proteins 2 and 4

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