Inhibitory Effect of Selective Cyclooxygenase-2 Inhibitor Lumiracoxib on Human Organic Anion Transporters hOAT1 and hOAT3

Abstract

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.

Effect of selective cyclooxygenase-2 inhibitor lumiracoxib on phenolsulfonphthalein disposition in rats

“…The effects of the selective cyclooxyganase-2 inhibitors on the disposition of methotrexate are therefore of interest. Although Hartmann et al reported no effect of lumiracoxib on the disposition of methotrexate in rheumatoid arthritis patients [7], we found that lumiracoxib inhibited human OAT1 (hOAT1) and hOAT3 strongly [8]. The goal of this study was to examine whether lumiracoxib influences renal OATs in vivo.…”

“…Sakurai et al reported that hOAT1 and hOAT3 transported PSP [9]. Lumiracoxib exhibited the inhibitory potencies against both transporters, and it was in a competitive manner [8]. Accordingly, it is considered that OAT1 and OAT3, expressed at the basolateral membrane in the proximal epithelial cells, mediated the renal tubular uptake of PSP from blood and that lumiracoxib inhibited it competitively in rats.…”

Enantioselective Drug Recognition by Drug Transporters

“…The interaction is fatal when high-dose methotrexate therapy is given to a patient [66,67]. Previous studies demonstrated the inhibitory effects of NSAIDs, including cyclooxygenase-2 inhibitors, on methotrexate uptake by OAT1 and OAT3 [68,69,70,71,72]. Some NSAIDs are chiral (Figure 1).…”