title: Human organic anion transporters 1 (hOAT1/SLC22A6) and 3 (hOAT3/SLC22A8) transport edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one) and its sulfate conjugate.
abstract: 3-Methyl-1-phenyl-2-pyrazolin-5-one (MCI-186; edaravone), a novel free radical scavenger, is used for the treatment of acute cerebral infarction. After marketing, a few cases of acute renal failure were reported in patients following treatment with this drug. Because edaravone is mainly excreted into the urine following conjugation to glucuronide or sulfate, the renal excretion mechanisms of edaravone should help provide important information when considering the clinical cases. We examined the transport of edaravone and its sulfate and glucuronide conjugates via human organic anion transporter 1 (hOAT1) and 3 (hOAT3), expressed on the basolateral membranes of proximal tubules. The hOAT1- and hOAT3-transfected human embryonic kidney (HEK)-293 cells exhibited a markedly higher uptake of edaravone sulfate and a slightly higher uptake of edaravone than vector-transfected cells. The K(m) values of edaravone sulfate uptake by hOAT1 and hOAT3 were 11 and 15 microM, respectively. Estimation of the relative contribution of hOAT1 and hOAT3 using reference compounds suggested that hOAT1 and hOAT3 might contribute to the renal uptake of edaravone sulfate to the same extent. However, edaravone and its sulfate showed no cytotoxicity toward both hOAT1-HEK and control cells, suggesting that higher uptake in hOAT1-HEK did not associate with cytotoxicity of these compounds. In conclusion, our results suggest that both hOAT1 and hOAT3 are responsible for the basolateral uptake of edaravone sulfate in the kidney.
authors.affiliation: Pharmacokinetics Laboratory, Mitsubishi Pharma Corporation, Chiba, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Mizuno
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Iwase
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Takuro
authors.initials: T
authors.lastname: Niwa
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000983:Antipyrine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D001692:Biological Transport; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D007700:Kinetics; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D013463:Sulfuric Acid Esters / Q000378:metabolism*; D014162:Transfection
chemical_list: D016166:Free Radical Scavengers; D020719:Glucuronides; D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D013463:Sulfuric Acid Esters; C114338:organic anion transport protein 3; D000077553:Edaravone; D000983:Antipyrine