RT Journal Article
SR Electronic
T1 CHARACTERIZATION OF THE RENAL TUBULAR TRANSPORT OF ZONAMPANEL, A NOVEL α-AMINO-3-HYDROXY-5-METHYLISOXAZOLE-4-PROPIONIC ACID RECEPTOR ANTAGONIST, BY HUMAN ORGANIC ANION TRANSPORTERS
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1096
OP 1102
DO 10.1124/dmd.32.10.1096
VO 32
IS 10
A1 Tadashi Hashimoto
A1 Shinichi Narikawa
A1 Xiu-Lin Huang
A1 Tsuyoshi Minematsu
A1 Takashi Usui
A1 Hidetaka Kamimura
A1 Hitoshi Endou
YR 2004
UL http://dmd.aspetjournals.org/content/32/10/1096.abstract
AB 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 α-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 μM, 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. The American Society for Pharmacology and Experimental Therapeutics