title: Characterization of the renal tubular transport of zonampanel, a novel alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, by human organic anion transporters.
abstract: Zonampanel monohydrate (YM872; [2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl]acetic acid monohydrate) is a novel alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist. The major elimination route for zonampanel has been reported to be by urine via the kidneys. The purpose of this study is to elucidate the molecular mechanism of the renal excretion of zonampanel using cells stably expressing human organic anion transporters (hOAT) 1, hOAT2, hOAT3, and hOAT4, as well as human organic cation transporters (hOCT) 1 and hOCT2. Another AMPA receptor antagonist, YM90K [6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione monohydrochloride], a decarboxymethylated form of zonampanel, was also used for comparing the substrate specificity. Zonampanel inhibited the uptake of prototypical organic anion substrates, [14C]para-aminohippurate in hOAT1 and [3H]estrone sulfate in hOAT3 and hOAT4, in a competitive manner. A time- and concentration-dependent increase in [14C]zonampanel uptake was observed in cells expressing hOAT1, hOAT3, and hOAT4. The Km values of zonampanel uptake by hOAT1, hOAT3, and hOAT4 were 1.4, 7.7, and 215 microM, respectively. Considering the localization of each transporter, results suggest that zonampanel is taken up via hOAT1 and hOAT3 from the blood into proximal tubular cells and then effluxed into the lumen via hOAT4. Probenecid and cimetidine competitively inhibited [14C]zonampanel uptake by the hOATs (hOAT1, hOAT3, and hOAT4 for probenecid; hOAT3 for cimetidine). YM90K inhibited the uptake of the prototypical substrate via hOAT3 competitively, but the uptake via hOAT1 noncompetitively. These findings suggest that the prototypical organic anion substrates (para-aminohippurate and estrone sulfate), cimetidine, probenecid, and zonampanel share binding specificity in each hOAT, whereas YM90K does not in hOAT1, possibly due to it being the decarboxymethylated form.
authors.affiliation: Drug Metabolism Laboratories, Drug Development Division, Yamanouchi Pharmaceutical Co., Ltd., 1-8, Azusawa 1-chome, Itabashi-ku, Tokyo 174-8511, Japan. hashimoto.tadashi@yamanouchi.co.jp
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Shinichi
authors.initials: S
authors.lastname: Narikawa
authors.forename: Xiu-Lin
authors.initials: XL
authors.lastname: Huang
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Minematsu
authors.forename: Takashi
authors.initials: T
authors.lastname: Usui
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Kamimura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Endou
mesh_terms: D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000378:metabolism*; D011810:Quinoxalines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007093:Imidazoles; D027361:Organic Anion Transporters; D011810:Quinoxalines; D018091:Receptors, AMPA; C110629:YM 872