Abstract
The overall disposition and hepatobiliary transport of BQ-123, an anionic cyclopentapeptide, and three analogs were examined in rats in vivo. Total body clearance (CLtotal) and biliary excretion clearance (CLbile, p) exhibited 4- to 8-fold differences between the compounds, with those for BQ-485 and compound A having the highest and lowest values, respectively. The CLbile, p values of BQ-485, BQ-123, and BQ-518 were almost equal to theCLtotal, suggesting that hepatobiliary transport is the major elimination pathway for these compounds. Hepatic uptake clearance (CLuptake, vivo) and biliary excretion clearance (CLbile, h/fT), which was defined for the hepatic unbound concentration, were separately determined to examine the hepatic uptake and excretion processes, respectively. Both theCLuptake, vivo andCLbile, h/fT of BQ-485 were higher than those of BQ-123, whereas the corresponding values for BQ-518 were similar to those for BQ-123. TheCLuptake, vivo andCLbile, h/fT of compound A were, respectively, approximately two thirds and one half those of BQ-123, suggesting that the lower CLbile, pvalue is due to the low efficiency of both the uptake and excretion processes. The CLuptake, vivo of these four peptides in vivo was similar to the extrapolated values based on the carrier-mediated transport activity previously assessed in vitro in isolated rat hepatocytes. The primary active transport previously assessed in an in vitro study in canalicular membrane vesicles was also highest for BQ-485 and lowest for compound A, similar toCLbile, h/fT in vivo. Thus, the transporters on both the sinusoidal and canalicular membranes determine the efficiency of the peptide overall elimination from the circulation.
Footnotes
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Send reprint requests to: Dr. Yukio Kato, Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: kato{at}seizai.f.u-tokyo.ac.jp
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1 This study was supported in part by a grant-in-aid for Scientific Research provided by the Ministry of Education, Science and Culture of Japan and in part by Core Research for Evolutional Science and Technology of Japan Science and Technology Corporation (J.S.T.).
- Abbreviations:
- CMV
- canalicular membrane vesicle
- cMOAT
- canalicular multispecific organic anion transporter
- HPLC
- high-performance liquid chromatography
- fu
- the plasma unbound fraction
- Rb
- blood-to-plasma concentration ratio
- fT
- unbound fraction in the liver
- PScell
- permeability surface area product across the isolated hepatocytes
- PS1
- the influx clearance across basolateral membrane
- PS2
- the efflux clearance across the basolateral membrane
- Received June 1, 1998.
- Accepted September 9, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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