OATP1B1, OATP1B3, and mrp2 are involved in hepatobiliary transport of olmesartan, a novel angiotensin II blocker.
Hepatic uptake and biliary excretion of olmesartan, a new angiotensin II blocker, were investigated in vitro using human hepatocytes, cells expressing uptake transporters and canalicular membrane vesicles, and in vivo using Eisai hyperbilirubinemic rats (EHBR), inherited multidrug resistance-associated protein (mrp2)-deficient rats. The uptake by human hepatocytes reached saturation with a Michaelis constant (K(m)) of 29.3 +/- 9.9 microM. Both Na(+)-dependent and Na(+)-independent uptake of olmesartan by human hepatocytes were observed. The uptake by Na(+)-independent human liver-specific organic anion transporters OATP1B1 and OATP1B3 expressed in Xenopus laevis oocytes was also saturable, with K(m) values of 42.6 +/- 28.6 and 71.8 +/- 21.6 microM, respectively. The Na(+)-dependent taurocholate-cotransporting polypeptide expressed in HEK 293 cells did not transport olmesartan. The cumulative biliary excretion in EHBR was one-sixth compared with that in Sprague-Dawley rats. ATP-dependent uptake of olmesartan was observed in both human canalicular membrane vesicles (hCMVs) and MRP2-expressing vesicles. An MRP inhibitor, MK-571 ([[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl][3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid) completely inhibited the uptake of olmesartan by hCMVs. In conclusion, the hepatic uptake and biliary excretion of olmesartan are mediated by transporters in humans. OATP1B1 and OATP1B3 are involved in hepatic uptake, at least in part, and MRP2 plays a dominant role in the biliary excretion.
Nakagomi-Hagihara
Rie
R
Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Tokyo, 140-8710, Japan.
Nakai
Daisuke
D
Kawai
Kenji
K
Yoshigae
Yasushi
Y
Tokui
Taro
T
Abe
Takaaki
T
Ikeda
Toshihiko
T
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism*; D001648:Bile Canaliculi / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012269:Ribosomal Proteins / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013777:Tetrazoles / Q000378:metabolism*; D014982:Xenopus laevis
D007093:Imidazoles; D027381:Liver-Specific Organic Anion Transporter 1; C093947:MRP2 protein, S cerevisiae; D024101:Mitochondrial Proteins; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D012269:Ribosomal Proteins; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D029701:Saccharomyces cerevisiae Proteins; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013777:Tetrazoles; D000804:Angiotensin II; C437965:olmesartan