Received for publication December 5, 2007.
Revised April 24, 2008.
Accepted for publication April 25, 2008.

ROLE OF ORGANIC ANION TRANSPORTERS IN THE PHARMACOKINETICS OF ZONAMPANEL, AN -AMINO-3-HYDROXY-5-METHYLISOXAZOLE-4-PROPIONATE RECEPTOR ANTAGONIST, IN RATS

Abstract

Zonampanel monohydrate (YM872) is a novel -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist. In humans, almost all administered zonampanel is excreted in the urine unchanged. Further, zonampanel is transported by human organic anion transporter 1 (OAT1), OAT3 and OAT4, 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 intravenously 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 µM. 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 µM). 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 inter-species 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.

Key words: drug interactions, drug transport, drug-drug interactions, excretion, hepatobiliary transport, organic anion transport, renal elimination, transporters