title: 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.
authors.affiliation: Laboratory of Clinical Pharmacodynamics, School of Pharmacy, Aichi Gakuin University, Nagoya, Japan. yuuwai＠dpc.agu.ac.jp
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Uwai
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Honjo
authors.forename: Kikuo
authors.initials: K
authors.lastname: Iwamoto
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D000077613:Etoricoxib; D006801:Humans; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000494:pharmacology; D007700:Kinetics; D007783:Lactones / Q000494:pharmacology; D008727:Methotrexate / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D018075:RNA, Complementary / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D014982:Xenopus laevis; D010130:p-Aminohippuric Acid / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors; D004008:Diclofenac; D004970:Estrone; D000077613:Etoricoxib; D007555:Isoxazoles; D007783:Lactones; D008727:Methotrexate; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D011720:Pyrazoles; D011725:Pyridines; D018075:RNA, Complementary; D013449:Sulfonamides; D013450:Sulfones; D010130:p-Aminohippuric Acid; C114338:organic anion transport protein 3; C116926:rofecoxib; C406224:valdecoxib; D000096926:Benzenesulfonamides; C017296:estrone sulfate; C473384:lumiracoxib