Interactions of nonsteroidal anti-inflammatory drugs with rat renal organic anion transporter, OAT-K1.
We recently cloned and characterized the rat kidney-specific organic anion transporter, OAT-K1, which was suggested to mediate renal tubular transport of methotrexate. In this study, we investigated the interactions of nonsteroidal anti-inflammatory drugs (NSAIDs) with OAT-K1 by evaluating the effects of these drugs on renal distribution of methotrexate in vivo, and on methotrexate accumulation in the stably transfected LLC-PK1 cells expressing OAT-K1 (LLC-OAT-K1). NSAIDs such as indomethacin and ketoprofen had significant inhibitory effects on renal accumulation of methotrexate in rats after coadministration. Indomethacin and ketoprofen inhibited methotrexate accumulation by LLC-OAT-K1 cells in a competitive manner with the apparent inhibition constant values of 1. 0 mM and 1.9 mM, respectively. Other NSAIDs including ibuprofen, flufenamate and phenylbutazone also showed potent inhibitory effects on methotrexate accumulation. However, indomethacin was not transported via OAT-K1. These results indicate that NSAIDs have potent inhibitory effects against the OAT-K1-mediated methotrexate transport, which suggests that the OAT-K1 may be one of interaction sites for methotrexate and NSAIDs in the kidney.
Masuda
S
S
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-01, Japan.
Saito
H
H
Inui
K I
KI
D000818:Animals; D027321:Anion Transport Proteins; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002352:Carrier Proteins / Q000187:drug effects*; D004347:Drug Interactions; D007213:Indomethacin / Q000493:pharmacokinetics / Q000494:pharmacology; D007660:Ketoprofen / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008727:Methotrexate / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013757:Tetraethylammonium Compounds / Q000493:pharmacokinetics
D027321:Anion Transport Proteins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002352:Carrier Proteins; D013757:Tetraethylammonium Compounds; D007660:Ketoprofen; D007213:Indomethacin; D008727:Methotrexate