title: Carrier-mediated hepatic uptake of peptidic endothelin antagonists in rats.
abstract: The endothelin antagonist BQ-123, an anionic cyclopentapeptide, is taken up by rat hepatocytes through active transport systems. Here, we have examined the hepatocellular uptake mechanism for several BQ-123 derivatives with anionic charges using isolated rat hepatocytes. BQ-485, a linear peptide, BQ-518, a cyclic peptide, and compound A, a cyclic peptide with a cationic moiety, 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-dependent, suggesting that active transport mechanisms are involved in their uptake into hepatocytes. BQ-485, BQ-518, and compound A can almost completely inhibit both the Na(+)-dependent and -independent uptake of [(3)H]BQ-123, with inhibition constants (K(i)) that are comparable to the Michaelis-Menten constants (K(m)) for their Na(+)-dependent and -independent uptake, respectively. Inhibition by BQ-485 was competitive, and the uptake of BQ-485 can be inhibited by BQ-123, with K(i) 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(+)-independent basolateral organic anion-transporting polypeptide (oatp1) was minimal. Thus, these three peptides share the transporters that also recognize BQ-123 but appear to differ from Ntcp and oatp1.
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Akhteruzzaman
authors.forename: Y
authors.initials: Y
authors.lastname: Kato
authors.forename: H
authors.initials: H
authors.lastname: Kouzuki
authors.forename: H
authors.initials: H
authors.lastname: Suzuki
authors.forename: A
authors.initials: A
authors.lastname: Hisaka
authors.forename: B
authors.initials: B
authors.lastname: Stieger
authors.forename: P J
authors.initials: PJ
authors.lastname: Meier
authors.forename: Y
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D018685:Anesthetics, Inhalation / Q000493:pharmacokinetics; D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001381:Azepines / Q000493:pharmacokinetics; D001667:Binding, Competitive; D001693:Biological Transport, Active; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D065128:Endothelin Receptor Antagonists; D004987:Ethers / Q000493:pharmacokinetics; D006845:Hydrocarbons, Fluorinated / Q000493:pharmacokinetics; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009842:Oligopeptides / Q000493:pharmacokinetics; D010455:Peptides / Q000493:pharmacokinetics*; D010456:Peptides, Cyclic / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
chemical_list: D018685:Anesthetics, Inhalation; D000959:Antihypertensive Agents; D001381:Azepines; D002352:Carrier Proteins; D065128:Endothelin Receptor Antagonists; D004987:Ethers; D006845:Hydrocarbons, Fluorinated; D009842:Oligopeptides; D010455:Peptides; D010456:Peptides, Cyclic; C117267:cyclo(tryptophyl-aspartyl-prolyl-thianylglycyl-leucyl); C083116:BQ 485; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; C072247:cyclo(Trp-Asp-Pro-Val-Leu)