TY - JOUR T1 - Species Differences in the Transport Activity for Organic Anions across the Bile Canalicular Membrane JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1324 LP - 1330 VL - 290 IS - 3 AU - Hitoshi Ishizuka AU - Kumiko Konno AU - Tetsuo Shiina AU - Hideo Naganuma AU - Kenji Nishimura AU - Kousei Ito AU - Hiroshi Suzuki AU - Yuichi Sugiyama Y1 - 1999/09/01 UR - http://jpet.aspetjournals.org/content/290/3/1324.abstract N2 - 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. TheKm and Vmaxvalues 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 μM 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 (Vmax/Km) 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. The American Society for Pharmacology and Experimental Therapeutics ER -