Ishizuka H, Konno K, Shiina T, Naganuma H, Nishimura K, Ito K, Suzuki H, Sugiyama Y
Analytical and Metabolic Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
J Pharmacol Exp Ther. 1999 Sep;290(3):1324-30.
Species differences in the transport activity mediated by canalicular multispecific organic anion transporter (cMOAT) were examined using temocaprilat, an angiotensin-converting enzyme inhibitor whose biliary excretion is mediated predominantly by cMOAT, and 2,4-dinitrophenyl-S-glutathione, a typical substrate for cMOAT, in a series of in vivo and in vitro experiments. Temocaprilat was infused to examine the biliary excretion rate at steady-state. The in vivo transport clearance values across the bile canalicular membrane, defined as the biliary excretion rate divided by the hepatic unbound concentrations, were 9.8, 39.2, 9.2, 1.1, and 0.8 ml/min/kg for mouse, rat, guinea pig, rabbit, and dog, respectively. The K(m) and V(max) values for ATP-dependent uptake of 2, 4-dinitrophenyl-S-glutathione into canalicular membrane vesicles were 15.0, 29.6, 16.1, 55.8, and 30.0 microM and 0.38, 1.90, 0.15, 0. 47, and 0.23 nmol/min/mg protein, yielding the in vitro transport clearance across the bile canalicular membrane (V(max)/K(m)) of 25.5, 64.2, 9.4, 8.4, and 7.7 for mouse, rat, guinea pig, rabbit, and dog, respectively. A close in vivo and in vitro correlation was observed among animal species for the transport clearance across the bile canalicular membrane. These results suggest that the uptake experiments with canalicular membrane vesicles can be used to quantitatively predict in vivo excretion across the bile canalicular membrane.
使用替莫卡普利（一种血管紧张素转换酶抑制剂，其胆汁排泄主要由小管多特异性有机阴离子转运体（cMOAT）介导）和2,4-二硝基苯基-S-谷胱甘肽（cMOAT的一种典型底物），通过一系列体内和体外实验研究了由cMOAT介导的转运活性的物种差异。输注替莫卡普利以检查稳态时的胆汁排泄率。跨胆小管膜的体内转运清除率值定义为胆汁排泄率除以肝脏未结合浓度，小鼠、大鼠、豚鼠、兔子和狗的该值分别为9.8、39.2、9.2、1.1和0.8 ml/min/kg。2,4-二硝基苯基-S-谷胱甘肽依赖ATP摄取进入胆小管膜囊泡的K(m)和V(max)值分别为15.0、29.6、16.1、55.8和30.0 microM以及0.38、1.90、0.15、0.47和0.23 nmol/min/mg蛋白，由此得出小鼠、大鼠、豚鼠、兔子和狗跨胆小管膜的体外转运清除率（V(max)/K(m)）分别为25.5、64.2、9.4、8.4和7.7。在不同动物物种之间观察到跨胆小管膜的转运清除率在体内和体外具有密切相关性。这些结果表明，使用胆小管膜囊泡进行的摄取实验可用于定量预测跨胆小管膜的体内排泄。
