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Vol. 290, Issue 3, 1324-1330, September 1999

Species Differences in the Transport Activity for Organic Anions across the Bile Canalicular Membrane1

Hitoshi Ishizuka, Kumiko Konno, Tetsuo Shiina, Hideo Naganuma, Kenji Nishimura, Kousei Ito, Hiroshi Suzuki and Yuichi Sugiyama

Analytical and Metabolic Research Laboratories (H.I., K.K., H.N., K.N.) and Biomedical Research Laboratories (T.S.), Sankyo Co., Ltd., Tokyo, Japan; and Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (K.I., H.S., Y.S.)

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 Km and Vmax 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 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.

0022-3565/99/2903-1324$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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