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Vol. 302, Issue 2, 666-671, August 2002
Department of Pharmacology and Toxicology, Kyorin University School
of Medicine, Tokyo, Japan.
Life-threatening drug interactions are known to occur between
methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs), probenecid, and penicillin G. The purpose of this study was to characterize methotrexate transport, as well as to determine the site
and the mechanism of drug interactions in the proximal tubule. Mouse
proximal tubule cells stably expressing basolateral human organic anion
transporters (hOAT1 and hOAT3) and apical hOAT (hOAT4) were
established. The Km values for hOAT1-,
hOAT3-, and hOAT4-mediated methotrexate uptake were 553.8 µM, 21.1 µM, and 17.8 µM, respectively. NSAIDs (salicylate, ibuprofen,
ketoprofen, phenylbutazone, piroxicam, and indomethacin), probenecid,
and penicillin G dose dependently inhibited methotrexate uptake
mediated by hOAT1, hOAT3, and hOAT4. Kinetic analysis of inhibitory
effects of these drugs on hOAT3-mediated methotrexate uptake revealed
that these inhibitions were competitive. The
Ki values for the effects of salicylate,
phenylbutazone, indomethacin, and probenecid on hOAT3-mediated
methotrexate uptake were comparable with therapeutically relevant
plasma concentrations of unbound drugs. In addition, in the presence of
human serum albumin, the Ki values were
comparable with therapeutically relevant total plasma concentrations of
drugs. In conclusion, these results suggest that methotrexate is taken
up via hOAT3 and hOAT1 at the basolateral side of the proximal tubule
and effluxed or taken up at the apical side via hOAT4. In addition,
hOAT1, hOAT3, and hOAT4 are the sites of drug interactions between
methotrexate and NSAIDs, probenecid, and penicillin G. Furthermore, it
was predicted that hOAT3 is the site of drug interactions between
methotrexate and salicylate, phenylbutazone, indomethacin, and
probenecid in vivo.
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