Contribution of organic anion transporting polypeptide OAPT-C to hepatic elimination of the opioid pentapeptide analogue [D-Ala2,D-Leu5]-enkephalin

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. [H-3]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 [H-3]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 [H-3]DADLE was observed. Moreover, the inhibitory effects of various compounds, including some peptides, on [H-3]estrone-3-sulfate uptake by OATP-C were similar to those observed in [H-3]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.