PT  - JOURNAL ARTICLE
AU  - Rie Nakagomi-Hagihara
AU  - Daisuke Nakai
AU  - Kenji Kawai
AU  - Yasushi Yoshigae
AU  - Taro Tokui
AU  - Takaaki Abe
AU  - Toshihiko Ikeda
TI  - OATP1B1, OATP1B3, AND MRP2 ARE INVOLVED IN HEPATOBILIARY TRANSPORT OF OLMESARTAN, A NOVEL ANGIOTENSIN II BLOCKER
AID  - 10.1124/dmd.105.008888
DP  - 2006 May 01
TA  - Drug Metabolism and Disposition
PG  - 862--869
VI  - 34
IP  - 5
4099  - http://dmd.aspetjournals.org/content/34/5/862.short
4100  - http://dmd.aspetjournals.org/content/34/5/862.full
SO  - Drug Metab Dispos2006 May 01; 34
AB  - 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 (Km) of 29.3 ± 9.9 μM. 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 Km values of 42.6 ± 28.6 and 71.8 ± 21.6 μM, 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. The American Society for Pharmacology and Experimental Therapeutics