Nakagomi-Hagihara Rie, Nakai Daisuke, Kawai Kenji, Yoshigae Yasushi, Tokui Taro, Abe Takaaki, Ikeda Toshihiko
Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Tokyo, 140-8710, Japan.
Drug Metab Dispos. 2006 May;34(5):862-9. doi: 10.1124/dmd.105.008888. Epub 2006 Feb 24.
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.
使用人肝细胞、表达摄取转运蛋白的细胞和胆小管膜囊泡在体外研究了新型血管紧张素II阻滞剂奥美沙坦的肝脏摄取和胆汁排泄，并使用卫材高胆红素血症大鼠（EHBR）、遗传性多药耐药相关蛋白（mrp2）缺陷大鼠在体内进行了研究。人肝细胞的摄取达到饱和，米氏常数（K(m)）为29.3±9.9微摩尔。观察到人肝细胞对奥美沙坦的Na(+)依赖性和Na(+)非依赖性摄取。非洲爪蟾卵母细胞中表达的Na(+)非依赖性人肝脏特异性有机阴离子转运蛋白OATP1B1和OATP1B3的摄取也具有饱和性，K(m)值分别为42.6±28.6和71.8±21.6微摩尔。在HEK 293细胞中表达的Na(+)依赖性牛磺胆酸盐共转运多肽不转运奥美沙坦。与Sprague-Dawley大鼠相比，EHBR中的累积胆汁排泄为六分之一。在人胆小管膜囊泡（hCMV）和表达MRP2的囊泡中均观察到ATP依赖性的奥美沙坦摄取。一种MRP抑制剂MK-571（[[[3-[2-(7-氯-2-喹啉基)乙烯基]苯基][3-(二甲基氨基)-3-氧代丙基]硫代]甲基]硫代]-丙酸）完全抑制了hCMV对奥美沙坦的摄取。总之，奥美沙坦的肝脏摄取和胆汁排泄在人体内由转运蛋白介导。OATP1B1和OATP1B3至少部分参与肝脏摄取，而MRP2在胆汁排泄中起主导作用。
