Stereoselective inhibitory effect of flurbiprofen, ibuprofen and naproxen on human organic anion transporters hOAT1 and hOAT3

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.