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

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Abstract
Methotrexate (MTX) has been used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of inflammatory diseases as well as malignancies. Especially at high MTX dosages, severe adverse effects with this combination may occur, usually resulting from an impaired renal elimination. It has been shown that the mechanism of this interaction cannot be fully attributed to inhibition of basolateral MTX uptake in renal proximal tubules. Here, we studied the effect of various NSAIDs on MTX transport in membrane vesicles isolated from cells overexpressing the proximal tubular apical efflux transporters human multidrug resistance protein (MRP) 2/ABCC2 and MRP4/ABCC4. MTX was transported by MRP2 and MRP4 with Km values of 480 ± 90 and 220 ± 70 μM, respectively. The inhibitory potency of the NSAIDs was generally higher against MRP4- than MRP2-mediated MTX transport, with therapeutically relevant IC50 values, ranging from approximately 2 μM to 1.8 mM. Salicylate, piroxicam, ibuprofen, naproxen, sulindac, tolmetin, and etodolac inhibited MRP2- and MRP4-mediated MTX transport according to a one-site competition model. In some cases, more complex interaction patterns were observed. Inhibition of MRP4 by diclofenac and MRP2 by indomethacin and ketoprofen followed a two-site competition model. Phenylbutazone stimulated MRP2 and celecoxib MRP4 transport at low concentrations and inhibited both transporters at high concentration. Our data suggest that the inhibition by NSAIDs of renal MTX efflux via MRP2 and MRP4 is a potential new site and mechanism contributing to the overall interaction between these drugs.

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