Carrier-mediated hepatic uptake of peptidic endothelin antagonists in rats

The endothelin antagonist BQ-123, an anionic cyclopentapeptide, is taken up by rat hepatocytes through active transport systems. Here, we have examine d the hepatocellular uptake mechanism for several BQ-123 derivatives with a nionic charges using isolated rat hepatocytes. BQ-485, a linear peptide, BQ -518, a cyclic peptide, and compound A, a cyclic peptide with a cationic mo iety, were taken up by hepatocytes in a concentration-dependent manner. The uptake of BQ-485 was most efficient, whereas compound A showed comparable uptake with BQ-123. The uptake of these peptides was Na+- and energy-depend ent, suggesting that active transport mechanisms are involved in their upta ke into hepatocytes. BQ-485, BQ-518, and compound A can almost completely i nhibit both the Na+- dependent and -independent uptake of [H-3]BQ-123, with inhibition constants (K-i) that are comparable to the Michaelis-Menten con stants (K-m) for their Na+-dependent and -independent uptake, respectively. Inhibition by BQ-485 was competitive, and the uptake of BQ-485 can be inhi bited by BQ-123, with Ki values that are comparable with the K-m values for BQ-123 uptake. The uptake of BQ-123 by COS-7 cells transfected with either Na+-dependent taurocholate-cotransporting polypeptide (Ntcp) or Na+-indepe ndent basolateral organic anion-transporting polypeptide (oatp1) was minima l. Thus, these three peptides share the transporters that also recognize BQ -123 but appear to differ from Ntcp and oatp1.