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CHARACTERIZATION OF THE RENAL TUBULAR TRANSPORT OF ZONAMPANEL, A NOVEL -AMINO-3-HYDROXY-5-METHYLISOXAZOLE-4-PROPIONIC ACID RECEPTOR ANTAGONIST, BY HUMAN ORGANIC ANION TRANSPORTERS

Drug Metabolism Laboratories, Drug Development Division, Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan (T.H., T.M., T.U., H.K.); Kobuchisawa Laboratories, Fuji Biomedix Co., Ltd., Yamanashi, Japan (S.N., X.-L.H.); and Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan (H.E.)

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 -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 K_m 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.

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				T. Minematsu, T. Hashimoto, T. Aoki, T. Usui, and H. Kamimura Role of Organic Anion Transporters in the Pharmacokinetics of Zonampanel, an {alpha}-Amino-3-hydroxy-5-methylisoxazole-4-propionate Receptor Antagonist, in Rats Drug Metab. Dispos., August 1, 2008; 36(8): 1496 - 1504. [Abstract] [Full Text] [PDF]

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