Characterization of renal tubular apical efflux of zonampanel, an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist, in humans.
1. Zonampanel, a novel alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist, is mainly excreted unchanged via renal tubular secretion. The renal apical transport transport of zonampanel was examined in this study using HEK293 cells expressing human organic anion transporter 4 (OAT4/SLC22A11), and membrane vesicles prepared from Sf-9 insect cells expressing human multidrug resistance-associated protein 2 (MRP2/ABCC2), MRP4 (ABCC4), and breast cancer resistance protein (BCRP/ABCG2). 2. Glutaric acid, a model dicarboxylate, trans-stimulated the uptake of [(14)C]zonampanel by OAT4, suggesting that zonampanel was transported by OAT4 via an exchange with dicarboxylate. Considering the endogenous dicarboxylate gradient, OAT4 seems to transport zonampanel in the direction of reabsorption rather than secretion. For MRP2, MRP4, and BCRP, zonampanel selectively inhibited the activity of MRP4 (K(i) = 41.3 microM). Marked transport of [(14)C]zonampanel was observed only for MRP4 (K(m) = 33.7 microM). 3. In conclusion, the data indicate that MRP4 was the apical efflux transporter that contributed to the active renal tubular secretion of zonampanel in humans, in concert with the apical reabsorption transporter OAT4 and basolateral uptake transporters.
Minematsu
T
T
Drug Metabolism Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tokyo, Japan. tsuyoshi.minematsu@jp.astellas.com
Hashimoto
T
T
Usui
T
T
Kamimura
H
H
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005977:Glutarates / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics*; D007684:Kidney Tubules / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D011810:Quinoxalines / Q000493:pharmacokinetics*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D022161:Transport Vesicles / Q000187:drug effects
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D005977:Glutarates; D007093:Imidazoles; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D029362:Organic Anion Transporters, Sodium-Independent; D011810:Quinoxalines; D018091:Receptors, AMPA; C000715087:ABCC2 protein, human; C073492:ABCC4 protein, human; C116614:ABCG2 protein, human; C498886:SLC22A9 protein, human; C110629:YM 872; C035736:glutaric acid