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.
The present study examined the possible role of transporters in the drug-drug interactions between methotrexate (MTX) and nonsteroidal anti-inflammatory drugs (NSAIDs) in the renal uptake process of MTX. MTX is recognized by reduced folate carrier (RFC-1) and rat organic anion transporters (rOat1 and rOat3) as a substrate. Uptake of MTX by kidney slices was saturable and inhibited potently by dibromosulfophthalein. Folate and benzylpenicillin (PCG) inhibited the uptake by 30 to 40% and 40 to 50% of the total saturable uptake of MTX by kidney slices, respectively, whereas the effect of p-aminohippurate (PAH) was minimal at the concentration selective for rOat1. In contrast, the uptake of 5-methyltetrahydrofolate by the kidney slices was inhibited by MTX, folate, and dibromosulfophthalein, but not by PAH and PCG. These results suggest that rOat3 and RFC-1 are almost equally involved in the uptake of MTX by the kidney slices, whereas RFC-1 is responsible for the renal uptake of 5-methyltetrahydrofolate. NSAIDs, except salicylate, were potent inhibitors of rOat3 (K(i) of 1.3-19 microM), but weak inhibitors of RFC-1 (K(i) of 70-310 microM). This is in a good agreement with the biphasic inhibition profiles of NSAIDs for the uptake of MTX by kidney slices. These results suggest that the renal uptake of MTX is not so greatly affected by NSAIDs as expected from the inhibition of rOat3-mediated transport.
Nozaki
Yoshitane
Y
Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku-Tokyo, 13-0033 Japan.
Kusuhara
Hiroyuki
H
Endou
Hitoshi
H
Sugiyama
Yuichi
Y
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology*; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D004347:Drug Interactions; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008727:Methotrexate / Q000493:pharmacokinetics / Q000494:pharmacology*; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D014316:Tritium
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002352:Carrier Proteins; D008565:Membrane Proteins; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C421043:Slc22a6 protein, rat; C114338:organic anion transport protein 3; D014316:Tritium; D008727:Methotrexate