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
- Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (Y.N., H.K., Y.S.); and Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan (H.E.)
- Address correspondence to:
Dr. Yuichi Sugiyama, Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyoku-Tokyo, 13-0033, Japan. E-mail: sugiyama{at}mol.f.u-tokyo.ac.jp
Abstract
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 (Ki of 1.3–19 μM), but weak inhibitors of RFC-1 (Ki of 70–310 μM). 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.
Footnotes
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This work was supported by grants-in-aid from the Ministry of Health, Labor and Welfare of Japan and from the Ministry of Education, Culture, Sports, Science and Technology of Japan for the 21st Century Center of Excellence (COE) program.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.103.061812.
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ABBREVIATIONS: MTX, methotrexate; NSAID, nonsteroidal anti-inflammatory drug; MDCK, Madin-Darby canine kidney; PAH, p-aminohippurate; PCG, benzylpenicillin; Oat/OAT, organic anion transporter; RFC-1, reduced folate carrier; 5-MTHF, 5-methyltetrahydrofolate; THF, tetrahydrofolate; TCA, taurocholate; DBSP, dibromosulfophthalein; Mrp, multidrug resistance-associated protein.
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- Received October 29, 2003.
- Accepted December 8, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
