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

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 human embryonic kidney 293 cells expressing organic anion-transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, and OAT3. We also observed its saturable uptake into human hepatocytes and kidney slices. Estimated from the relative activity factor method and application of 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/multidrug resistance-associated protein (MRP) 2 double transfectants, but not in OATP1B1/multidrug resistance (MDR) 1 and OATP1B1/ breast cancer resistance protein (BCRP) transfectants. ATP-dependent transport into membrane vesicles expressing human MRP2 and MRP4 was clearly observed, with K m values of 14.9 and 26.2 M, 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 double 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.

Pharmacokinetic interaction between pravastatin and olmesartan in relation to SLCO1B1 polymorphism

“…The mechanism by which urinary excretion of olmesartan was reduced after the co-administration of pravastatin is unclear and still needs to be clarified. Recent in vitro studies indicated that organic anion transporter 3 (OAT3) expressed at the basolateral membrane of renal proximal tubule epithelial cells is predominantly involved in renal uptake of both pravastatin and olmesartan (Hasegawa et al 2002;Yamada et al 2007). The drug-drug interaction via OAT3 between pravastatin and olmesartan may account for the reduction of olmesartan renal excretion in the co-administration phase; however, the interaction via MRP2, which also is expressed in the kidney, cannot be ruled out (Kivistö et al 2005;Nakagomi-Hagihara et al 2006).…”

“…Recent in vitro studies using OATP1B1-expressing Xenopus laevis oocytes (Nakagomi-Hagihara et al 2006) and HEK293 cells (Yamada et al 2007) have indicated that olmesartan is a substrate of OATP1B1. Olmesartan is eliminated from the body through hepatic and renal routes without extensive metabolism (Laeis et al 2001).…”

“…Olmesartan medoxomil is completely de-esterified during absorption to form olmesartan, a pharmacologically active metabolite, which is excreted by hepatobiliary and renal systems without further metabolism (Laeis et al 2001). At least two uptake transporters, OATP1B1 and OATP1B3, have been demonstrated to account for hepatic uptake of olmesartan (Nakagomi-Hagihara et al 2006;Yamada et al 2007). As pravastatin and olmesartan share some transporter-mediated transport pathways, such as hepatic uptake via OATP1B1, the co-administration of both drugs may potentially cause drug-drug interactions, which may consequently modulate the pharmacokinetics or pharmacodynamics of either drug.…”

Association study of genetic polymorphisms of drug transporters, SLCO1B1, SLCO1B3 and ABCC2, in African-Americans, Hispanics and Caucasians and olmesartan exposure

“…3 Therefore, the effect of genetic variations of single transporters on the pharmacokinetics of olmesartan is considered to be small.…”

“…1 Some studies have suggested that organic anion-transporting polypeptide 1B1 (gene name, SLCO1B1) and organic anion-transporting polypeptide 1B3 (SLCO1B3) are involved in hepatic uptake and that the ATP-binding cassette, sub-family C member 2 (multidrug resistance-associated protein (MRP) 2, ABCC2), is involved in the biliary excretion of olmesartan. 2,3 Membrane transporters have important roles in the uptake, distribution and excretion of endogenous compounds and xenobiotics. Polymorphisms in genes encoding transporters have been investigated extensively and appear to be associated with altered transporter activity.…”