PT  - JOURNAL ARTICLE
AU  - Yukio Kato
AU  - Sharif Akhteruzzaman
AU  - Akihiro Hisaka
AU  - Yuichi Sugiyama
TI  - Hepatobiliary Transport Governs Overall Elimination of Peptidic Endothelin Antagonists in Rats
DP  - 1999 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 568--574
VI  - 288
IP  - 2
4099  - http://jpet.aspetjournals.org/content/288/2/568.short
4100  - http://jpet.aspetjournals.org/content/288/2/568.full
SO  - J Pharmacol Exp Ther1999 Feb 01; 288
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics