Role of organic anion transporters in the pharmacokinetics of zonampanel, an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist, in rats.
Zonampanel monohydrate ([2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydro-1-quinoxalinyl] acetic acid monohydrate, YM872) is a novel alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist. In humans, almost all administered zonampanel is excreted in the urine unchanged. Furthermore, zonampanel is transported by human organic anion transporter (OAT) 1, and OAT3 but not by OAT2, suggesting the contribution of OATs to renal excretion. In rats also, zonampanel is predominantly eliminated via urine but partly also via bile as the unchanged form. In this study, the molecular mechanism of the excretion of zonampanel was elucidated using cells expressing rat Oat1, Oat2, and Oat3. Furthermore, zonampanel (15 mg/kg) was given i.v. to rats with or without probenecid (50 mg/kg) or cimetidine (40 mg/kg), and pharmacokinetic parameters were compared. Zonampanel inhibited the uptake of typical substrates by Oat1, Oat2, and Oat3 with inhibition constant (K(i)) values of 7.02 to 10.4 microM. A time- and saturable concentration-dependent increase in [14C]zonampanel uptake was observed in these cells [Michaelis-Menten constant (K(m)) values: 13.4 to 53.6 microM]. Probenecid and cimetidine inhibited [14C]zonampanel uptake by Oats. In in vivo experiments, probenecid and cimetidine decreased intrinsic clearance for both the renal secretion and biliary excretion of zonampanel. Considering the tissue distribution and localization of each transporter, these results suggest that in rats zonampanel is taken up from the blood into proximal tubular cells via Oat1 and Oat3 and, unlike the case in humans, also into hepatocytes via Oat2 and Oat3. The interspecies differences in the excretion of zonampanel between rats and humans may thus be explained by those in the substrate selectivity and tissue distribution of OATs.
Minematsu
Tsuyoshi
T
Drug Metabolism Research Laboratories, Astellas Pharma Inc., 1-8 Azusawa 1-chome, Itabashiku, Tokyo 174-8511, Japan. tsuyoshi.minematsu@jp.astellas.com
Hashimoto
Tadashi
T
Aoki
Toshiko
T
Usui
Takashi
T
Kamimura
Hidetaka
H
D000818:Animals; D002460:Cell Line; D002927:Cimetidine / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics*; D018374:LLC-PK1 Cells; D008297:Male; D027361:Organic Anion Transporters / Q000502:physiology*; D011339:Probenecid / Q000494:pharmacology; D011810:Quinoxalines / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D013552:Swine
D018691:Excitatory Amino Acid Antagonists; D007093:Imidazoles; D027361:Organic Anion Transporters; D011810:Quinoxalines; D018091:Receptors, AMPA; C110629:YM 872; D002927:Cimetidine; D011339:Probenecid