Received for publication June 27, 2007.
Revised August 7, 2007.
Accepted for publication September 5, 2007.

Multiple human isoforms of drug transporters contribute to the hepatic and renal transport of olmesartan, a selective antagonist of the angiotensin II AT1-receptor

Abstract

Olmesartan, a novel angiotensin II AT1-receptor antagonist, is excreted into both bile and urine, with minimal metabolism. Because olmesartan is a hydrophilic anionic compound, some transporters could be involved in its hepatic and renal clearance. In this study, we characterized the role of human drug transporters in the pharmacokinetics of olmesartan and determined the contribution of each transporter to the overall clearance of olmesartan. Olmesartan was significantly taken up into HEK293 cells expressing OATP1B1, OATP1B3, OAT1 and OAT3. We also observed its saturable uptake into human hepatocytes and kidney slices. Estimated from relative activity factor (RAF) method and specific inhibitors, the relative contributions of OATP1B1 and OATP1B3 to the uptake of olmesartan in human hepatocytes were almost the same, whereas OAT3 was predominantly involved in its uptake in kidney slices. The vectorial transport of olmesartan was observed in OATP1B1/MRP2 double transfectants, but not in OATP1B1/MDR1 and OATP1B1/BCRP transfectants. ATP-dependent transport into membrane vesicles expressing human MRP2 and MRP4 was clearly observed, with Km values of 14.9 and 26.2 µM, respectively, whereas the urinary excretion of olmesartan in Mrp4-knockout mice was not different from that of control mice. We also investigated the transcellular transport of olmesartan medoxomil, a prodrug of olmesartan. Vectorial basal-to-apical transport was observed in OATP1B1/MRP2, OATP1B1/MDR1 double and OATP1B1/BCRP transfectants, suggesting the possible involvement of MRP2, MDR1 and BCRP in the limit of intestinal absorption of olmesartan medoxomil. From these results, we suggest that multiple transporters make a significant contribution to the pharmacokinetics of olmesartan and its prodrug.

Key words: active transport, biliary excretion, drug transport, hepatic elimination, hepatic transport, hepatic uptake, hepatobiliary transport, organic anion transport, renal transport, transporters