Nonsteroidal anti-inflammatory drugs (NSAIDs) delay the renal excretion of antifolate methotrexate by inhibiting human organic anion transporters hOAT1 (SLC22A6) and hOAT3 (SLC22A8). In this study, uptake experiments were performed using Xenopus laevis oocytes to assess stereoselectivity in the inhibitory characteristics of flurbiprofen, ibuprofen and naproxen against hOAT1 and hOAT3. Uptake of p-aminohippurate by hOAT1 was inhibited by each enantiomer of the three NSAIDs, and the inhibitory effect was superior in each (S)-enantiomer around 10 µM. The apparent 50% inhibitory concentrations were estimated to be 0.615 µM for (S)-flurbiprofen, 2.84 µM for (S)-ibuprofen and 1.93 µM for (S)-naproxen, and these values were significantly lower than those of the respective (R)-enantiomers [(R)-flurbiprofen: 2.35 µM, (R)-ibuprofen: 6.14 µM, (R)-naproxen: 5.26 µM]. Furthermore, the (S)-NSAIDs at 3 µM reduced methotrexate accumulation in hOAT1-expressing oocytes more strongly than the corresponding (R)-enantiomers. All enantiomers inhibited hOAT3-mediated transport of estrone sulfate and methotrexate, but there was no difference between both enantiomers of each NSAID in the inhibitory potencies. Eadie-Hofstee plot analysis showed that (S)-flurbiprofen and (R)-flurbiprofen inhibited hOAT1 and hOAT3 in a competitive manner. These findings represent the stereoselective inhibitory potencies of flurbiprofen, ibuprofen and naproxen on hOAT1, and the (S)-enantiomers are greater. In contrast, stereoselectivity was not recognized in their inhibitory effect on hOAT3.
Several kinds of food have been shown to influence the absorption and metabolism of drugs, although there is little information about their effect on the renal excretion of drugs. In this study, we performed uptake experiments using Xenopus laevis oocytes to assess the inhibitory effects of chlorogenic acid, caffeic acid and quinic acid, which are contained in coffee, fruits and vegetables, on human organic anion transporters hOAT1 and hOAT3; these transporters mediate renal tubular uptake of anionic drugs from blood. Injection of hOAT1 and hOAT3 cRNA into oocytes stimulated uptake of typical substrates of hOAT1 and hOAT3 (p-aminohippurate and estrone sulfate, respectively); among the three compounds tested, caffeic acid most strongly inhibited these transporters. The apparent 50% inhibitory concentrations of caffeic acid were estimated to be 16.6 µM for hOAT1 and 5.4 µM for hOAT3. Eadie-Hofstee plot analysis showed that caffeic acid inhibited both transporters in a competitive manner. In addition to the transport of p-aminohippurate and estrone sulfate, that of antifolates and antivirals was inhibited by caffeic acid. These findings show that caffeic acid has inhibitory potential against hOAT1 and hOAT3, suggesting that renal excretion of their substrates could be affected in patients consuming a diet including caffeic acid.
Nonsteroidal anti-inflammatory drugs (NSAIDs) delay renal excretion of antifolate methotrexate by inhibiting human organic anion transporters hOAT1 (SLC22A6) and hOAT3 (SLC22A8). In this study, we performed uptake experiments using Xenopus laevis oocytes to assess the inhibitory effect of selective cyclooxygenase-2 inhibitors on hOAT1 and hOAT3. The uptake of methotrexate into oocytes was increased by the injection of hOAT1 and hOAT3 cRNA, and transport was strongly inhibited by lumiracoxib. The apparent 50% inhibitory concentrations of lumiracoxib were estimated to be 3.3 µM and 1.9 µM for uptake of p-aminohippurate by hOAT1 and of estrone sulfate by hOAT3, respectively. Eadie-Hofstee plot analysis showed that lumiracoxib inhibited hOAT1 and hOAT3 in a competitive manner. For other cyclooxygenase-2 inhibitors celecoxib, etoricoxib, rofecoxib and valdecoxib, slight to moderate inhibition of hOAT3 only was observed. These findings show that lumiracoxib has inhibitory potential toward hOAT1 and hOAT3, comparable to that of nonselective NSAIDs.
It is well known that nonsteroidal anti-inflammatory drugs (NSAIDs) delay the elimination of methotrexate. One of the mechanisms is thought to be inhibition of methotrexate uptake via human organic anion transporter 3 (hOAT3, SLC22A8) in the renal proximal tubule by NSAIDs. In this study, we evaluated the inhibitory effects of selective cyclooxygenase-2 inhibitor etoricoxib on hOAT3 by uptake experiments using Xenopus laevis oocytes. The injection of hOAT3 cRNA stimulated the uptake of methotrexate into the oocytes, and its transport was inhibited by etoricoxib. Etoricoxib inhibited estrone sulfate uptake by hOAT3 dose dependently, and the 50% inhibitory concentration was estimated to be 9.8 µM. Eadie-Hofstee plot analysis showed that etoricoxib inhibited hOAT3 in a competitive manner. These findings show that etoricoxib has inhibitory effect on hOAT3, and that the potential is comparable to that of traditional NSAIDs.
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