title: Contribution of organic anion transporting polypeptide OATP-C to hepatic elimination of the opioid pentapeptide analogue [D-Ala2, D-Leu5]-enkephalin.
abstract: The objective of this study was to examine the transport activity of the human organic anion transporter OATP-C (SLC21A6) for oligopeptides that are eliminated rapidly from the systemic circulation. We focused on an opioid peptide analogue, [D-Ala(2), D-Leu(5)]-enkephalin (DADLE), a linear pentapeptide modified to be stable. [(3)H]DADLE was taken up by rat isolated hepatocytes in a saturable manner and highly accumulated in the liver after intravenous administration to rats. The uptake of [(3)H]DADLE by the isolated hepatocytes was inhibited by several organic anions and pentapeptides, but not by tetra- or tripeptides. When OATP-C was expressed in Xenopus laevis oocytes, a significant increase in uptake of [(3)H]DADLE was observed. Moreover, the inhibitory effects of various compounds, including some peptides, on [(3)H]estrone-3-sulfate uptake by OATP-C were similar to those observed in [(3)H]DADLE uptake by rat isolated hepatocytes. In conclusion, it was demonstrated that OATP-C contributes to the rapid hepatic excretion of peptides and peptide-mimetic drugs.
authors.affiliation: Department of Pharmaceutical Biology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nozawa
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Sai
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Nezu
authors.forename: Akira
authors.initials: A
authors.lastname: Tsuji
mesh_terms: D000818:Animals; D000838:Anions; D001646:Bile; D001692:Biological Transport; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000493:pharmacokinetics; D016308:Enkephalin, Leucine-2-Alanine / Q000493:pharmacokinetics*; D004970:Estrone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D022781:Hepatocytes / Q000378:metabolism*; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D027381:Liver-Specific Organic Anion Transporter 1 / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D000838:Anions; D027381:Liver-Specific Organic Anion Transporter 1; D010455:Peptides; D004970:Estrone; D016308:Enkephalin, Leucine-2-Alanine; D020881:Enkephalin, D-Penicillamine (2,5)-; C017296:estrone sulfate