Interaction between methotrexate and nonsteroidal anti-inflammatory drugs in organic anion transporter.
The antifolate drug methotrexate is mainly eliminated from the body by renal tubular secretion via organic anion transporters. In clinical situations, severe methotrexate toxicity, due to an increase in serum concentrations, was observed after coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) or probenecid. In this study, we examined the effects of NSAIDs and probenecid on methotrexate transport via the rat renal organic anion transporter rOAT1, using Xenopus laevis oocytes. [3H]Methotrexate uptake was markedly stimulated in the rOAT1 cRNA-injected oocytes, and this uptake was inhibited by probenecid and various NSAIDs, whereas the influence of salicylate was less. The Dixon plots showed that probenecid, indomethacin and salicylate competitively inhibited rOAT1 with apparent K(i) values of 15.8 microM, 4.2 microM and 1.0 mM, respectively. These findings demonstrate that rOAT1 is the major site of the transporter-mediated interaction between methotrexate and NSAIDs and/or probenecid, leading to a decrease in renal excretion of methotrexate.
Uwai
Y
Y
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto 606-8507, Sakyo, Japan.
Saito
H
H
Inui
K
K
D000818:Animals; D027321:Anion Transport Proteins; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism*; D007700:Kinetics; D008727:Methotrexate / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011339:Probenecid / Q000494:pharmacology; D014528:Uricosuric Agents / Q000494:pharmacology; D014982:Xenopus laevis
D027321:Anion Transport Proteins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000964:Antimetabolites, Antineoplastic; D002352:Carrier Proteins; D014528:Uricosuric Agents; D011339:Probenecid; D008727:Methotrexate