Hepatobiliary transport mechanism for the cyclopentapeptide
endothelin antagonist bq-123.
Shin, Ho-Chul, Yukio Kato, Tadashi Yamada, Kayoko Niinuma, Akihiro
Hisaka, and Yuichi Sugiyama.
Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113, and Tsukuba Research Institute, Banyu
Pharmaceutical Co., Ltd., Okubo 3, Tsukuba 300-33, Japan
APStracts 3:0266G, 1996.
The hepatobiliary transport of an anionic cyclopentapeptide endothelin
antagonist, BQ-123 was studied in rats. Biliary excretion of [3H]BQ
-123 was extensive in vivo (approximately 75% of intravenous infusion
rates). Liver to plasma and bile to liver concentration ratios at
steady-state were approximately 3 and 200, respectively, suggesting
that both hepatic uptake and biliary excretion are concentrative
processes. The biliary excretion clearance exhibited a saturation at
a hepatic concentration higher than 100 nmol/g liver and was markedly
reduced in Eisai hyperbilirubinemic rats (EHBR) having a hereditary
defect of canalicular multispecific organic anion transporter
(cMOAT). An ATP-dependent and saturable uptake of BQ-123 by isolated
canalicular membrane vesicles (CMV) was observed in vitro. Impaired
transport of BQ-123 was also confirmed in CMV prepared from EHBR.
These results demonstrate that the biliary excretion process is ATP
-driven primary active transport. It is proposed that cMOAT is mainly
responsible for the biliary excretion of BQ-123.
Received 29 June 1995; accepted in final form 6 December 1996.
APS Manuscript Number G278-5.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 31 December 1996