Quantitative Evaluation of the Drug-Drug Interactions between Methotrexate and Nonsteroidal Anti-Inflammatory Drugs in the Renal Uptake Process Based on the Contribution of Organic Anion Transporters and Reduced Folate Carrier

Nozaki, Yoshitane; Kusuhara, Hiroyuki; Endou, Hitoshi; Sugiyama, Yuichi

doi:10.1124/jpet.103.061812

Cited by 69 publications

(58 citation statements)

References 29 publications

(34 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Renal tubular secretion involves different uptake transporters. A recent study showed that the basolateral localization of mouse reduced folate carrier (RFC-1) in the kidney is responsible for the uptake of MTX (Nozaki et al, 2004). Other uptake transporters that are mainly expressed in the liver (OATP1B) or intestine (OATP1A2) were found to transport MTX in vitro.…”

Section: Discussionmentioning

confidence: 99%

Proton Pump Inhibitors Inhibit Methotrexate Transport by Renal Basolateral Organic Anion Transporter hOAT3

et al. 2014

View full text Add to dashboard Cite

The coadministration of methotrexate (MTX) and proton pump inhibitors (PPIs) can result in a pharmacokinetic interaction that delays MTX elimination and subsequently increases the MTX blood concentrations. Human organic anion transporters (hOATs) are responsible for the renal tubular secretion of MTX and are thought to be involved in this drug interaction. The aim of this study was to evaluate the inhibitory potencies of PPIs on hOAT1 and hOAT3, which are the two isoforms of OATs predominantly expressed in kidney proximal tubules. Using stably transfected cell systems that express the uptake transporters human embryonic kidney (HEK)-hOAT1 and HEK-hOAT3, we analyzed the inhibitory potencies of omeprazole, lansoprazole, and pantoprazole on OAT-mediated [

show abstract

Section: Discussionmentioning

confidence: 99%

Proton Pump Inhibitors Inhibit Methotrexate Transport by Renal Basolateral Organic Anion Transporter hOAT3

et al. 2014

View full text Add to dashboard Cite

show abstract

“…[8][9][10][11] Multidrug resistance-related proteins (MRP) 2 and 4 and breast cancer-resistant protein (BCRP) transport MTX across the apical membrane into the urine where it is excreted. [12][13][14][15] Previous studies have shown that several mechanisms, including the inhibitory effect of NSAIDs on OATs and RFC-1-mediated MTX uptake at the basolateral membrane, 16,17) and MTX efflux via MRP2 and MRP4 at apical membrane in tubular cells, 18) are involved in the interaction between MTX and NSAIDs.…”

mentioning

confidence: 99%

Inhibition of Methotrexate Uptake <i>via</i> Organic Anion Transporters OAT1 and OAT3 by Glucuronides of Nonsteroidal Anti-inflammatory Drugs

Iwaki

Shimada

Irino

et al. 2017

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Combination therapy of non-steroidal anti-inflammatory drugs (NSAIDs) and methotrexate (MTX) sometimes triggers adverse effects, such as liver injury, renal failure, gastrointestinal disorders, and myelosuppression, owing to the reduction of MTX clearance. Previous reports have suggested that NSAIDs inhibit renal MTX uptake via organic anion transporters (OATs) and reduced folate transporter (RFC)-1 and efflux via multidrug resistance-associated proteins (MRPs). Recently, our laboratory found inhibitory effects of NSAIDs-glucuronide (NSAIDs-Glu), a major metabolite of NSAIDs, on MRP-mediated MTX transport as a new site of interaction between MTX and NSAIDs. However, it remains unclear that whether NSAIDsGlu inhibit renal uptake of MTX. Therefore, the present study aimed to evaluate inhibitory effects of several NSAIDs-Glu (diclofenac, R-and S-ibuprofen, R-and S-flurbiprofen, and R-and S-naproxen) on human OAT1 and OAT3-mediated MTX transport. In this study, [ 3 H]MTX uptake was observed by using human OAT1 and OAT3-overexpressing HEK293 cells in the presence or absence of NSAIDs-Glu. All examined NSAIDs-Glu exhibited concentration-dependent inhibitory effects on MTX uptake via OAT1 and OAT3. Our results indicated that NSAIDs-Glu are more potent (5-to 15-fold) inhibitors of OAT3 than OAT1. Moreover, stereoselective inhibitory effects of NSAIDs-Glu on OATs-mediated MTX uptake were not observed, unlike on MRPs-mediated transport. These findings suggest that inhibition of OAT1 and OAT3-mediated renal uptake of MTX by plasma NSAIDs-Glu may be one of the competitive sites underlying complex drug interaction between MTX and NSAIDs.Key words drug interaction; methotrexate; non-steroidal anti-inflammatory drug; glucuronide; organic anion transporter Although methotrexate (MTX) is often co-administered with non-steroidal anti-inflammatory drugs (NSAIDs) to patients suffering from rheumatoid arthritis and neoplastic diseases, several NSAIDs, such as ketoprofen, indomethacin, naproxen, and diclofenac, reduce MTX clearance. Thus, combined administration of MTX and NSAIDs can result in elevated plasma MTX concentrations and severe adverse effects, such as liver injury, renal failure, gastrointestinal disorders, and myelosuppression. [1][2][3][4][5] In fact, the MTX prescribers' information states that combined use of MTX and NSAIDs may increase plasma MTX concentrations and adverse effects.MTX is primarily excreted in urine via glomerular filtration and active tubular secretion in its unchanged form.6) At a clinical plasma concentration of MTX (0.2-10 µM), approximately 25% of renal clearance is excreted by glomerular filtration and the remaining 75% is excreted by active tubular secretion. 7)In the tubular secretory process, organic anion transporters (OAT) 1 and 3 and reduced folate carrier (RFC)-1 transport MTX from the blood across the basolateral membrane. [8][9][10][11] Multidrug resistance-related proteins (MRP) 2 and 4 and breast cancer-resistant protein (BCRP) transport MTX across the apical membrane into the urine w...

show abstract

“…Renal tubular secretion and reabsorption of folates in proximal tubules involves specific roles for folate transporters on the basolateral (e.g., OAT1, OAT3, RFC) and apical (e.g., OATP1, FR , MRP2, MRP4) membranes Nozaki et al, 2004). Folates are filtered via the glomerulus and reabsorbed by a FR -mediated endocytotic process, then transported into the bloodstream by folate transporters localized to the basolateral membrane.…”

Section: Folate Transport In Tissue Folate Homeostasis and Physimentioning

confidence: 99%

Chapter 5 Structure and Function of the Reduced Folate Carrier

Matherly

Hou

2008

Vitamins &Amp; Hormones

View full text Add to dashboard Cite

Folates are essential for life and folate deficiency contributes to a host of health problems including cardiovascular disease, fetal abnormalities, neurologic disorders, and cancer. Antifolates, represented by methotrexate, continue to occupy a unique niche among the modern day pharmacopoeia for cancer along with other pathologic conditions. This review focuses on the biology of the membrane transport system termed the "reduced folate carrier" or RFC with a particular emphasis on RFC structure and function. The ubiquitously expressed RFC is the major transporter for folates in mammalian cells and tissues. Loss of RFC expression or function portends potentially profound physiologic or developmental consequences. For chemotherapeutic antifolates used for cancer, loss of RFC expression or synthesis of mutant RFC protein with impaired function results in antifolate resistance due to incomplete inhibition of cellular enzyme targets and low levels of substrate for polyglutamate synthesis. The functional properties for RFC were first documented nearly 40 years ago in murine leukemia cells. Since 1994, when RFC was first cloned, tremendous advances in the molecular biology of RFC and biochemical approaches for studying the structure of polytopic membrane proteins have led to an increasingly detailed picture of the molecular structure of the carrier, including its membrane topology, its Nglycosylation, identification of functionally and structurally important domains and amino acids, and helix packing associations. Although no crystal structure for RFC is yet available, biochemical and molecular studies, combined with homology modeling, based on homologous bacterial Major Facilitator Superfamily transporters such as LacY, now permit the development of experimentally testable hypotheses designed to establish RFC structure and mechanism.

show abstract

Quantitative Evaluation of the Drug-Drug Interactions between Methotrexate and Nonsteroidal Anti-Inflammatory Drugs in the Renal Uptake Process Based on the Contribution of Organic Anion Transporters and Reduced Folate Carrier

Cited by 69 publications

References 29 publications

Proton Pump Inhibitors Inhibit Methotrexate Transport by Renal Basolateral Organic Anion Transporter hOAT3

Proton Pump Inhibitors Inhibit Methotrexate Transport by Renal Basolateral Organic Anion Transporter hOAT3

Inhibition of Methotrexate Uptake <i>via</i> Organic Anion Transporters OAT1 and OAT3 by Glucuronides of Nonsteroidal Anti-inflammatory Drugs

Chapter 5 Structure and Function of the Reduced Folate Carrier

Contact Info

Product

Resources

About