Vol. 288, Issue 2, 568-574, February 1999

Hepatobiliary Transport Governs Overall Elimination of Peptidic Endothelin Antagonists in Rats

Yukio Kato, Sharif Akhteruzzaman, Akihiro Hisaka and Yuichi Sugiyama

Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan (S.A., Y.K., Y.S.); and Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo, Tsukuba, Japan (A.H.)

The overall disposition and hepatobiliary transport of BQ-123, an anionic cyclopentapeptide, and three analogs were examined in rats in vivo. Total body clearance (CL_total) and biliary excretion clearance (CL_{bile, 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 CL_{bile, p} values of BQ-485, BQ-123, and BQ-518 were almost equal to the CL_total, suggesting that hepatobiliary transport is the major elimination pathway for these compounds. Hepatic uptake clearance (CL_{uptake, vivo}) and biliary excretion clearance (CL_{bile, h}/f_T), which was defined for the hepatic unbound concentration, were separately determined to examine the hepatic uptake and excretion processes, respectively. Both the CL_{uptake, vivo} and CL_{bile, h}/f_T of BQ-485 were higher than those of BQ-123, whereas the corresponding values for BQ-518 were similar to those for BQ-123. The CL_{uptake, vivo} and CL_{bile, h}/f_T of compound A were, respectively, approximately two thirds and one half those of BQ-123, suggesting that the lower CL_{bile, p} value is due to the low efficiency of both the uptake and excretion processes. The CL_{uptake, 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 to CL_{bile, h}/f_T in vivo. Thus, the transporters on both the sinusoidal and canalicular membranes determine the efficiency of the peptide overall elimination from the circulation.