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Uptake of Ursodeoxycholate and Its Conjugates by Human Hepatocytes:  Role of Na+-Taurocholate Cotransporting Polypeptide (NTCP), Organic Anion Transporting Polypeptide (OATP) 1B1 (OATP-C), and OATP1B3 (OATP8)

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Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan, and Department of Medicine, University of California, San Diego, California
Cite this: Mol. Pharm. 2006, 3, 1, 70–77
Publication Date (Web):December 15, 2005
https://doi.org/10.1021/mp050063u
Copyright © 2006 American Chemical Society

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    Abstract

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    Ursodeoxycholate (UDCA) is widely used for the treatment of cholestatic liver disease. After oral administration, UDCA is absorbed, taken up efficiently by hepatocytes, and conjugated mainly with glycine to form glycoursodeoxycholate (GUDC) or partly with taurine to form tauroursodeoxycholate (TUDC), which undergo enterohepatic circulation. In this study, to check whether three basolateral transportersNa+-taurocholate cotransporting polypeptide (NTCP, SLC10A1), organic anion transporting polypeptide (OATP) 1B1 (OATP-C), and OATP1B3 (OATP8)mediate uptake of UDCA, GUDC, and TUDC by human hepatocytes, we investigated their transport properties using transporter-expressing HEK293 cells and human cryopreserved hepatocytes. TUDC and GUDC could be taken up via human NTCP, OATP1B1, and OATP1B3, whereas UDCA could be transported significantly by NTCP, but not OATP1B1 and OATP1B3 in our expression systems. We observed a time-dependent and saturable uptake of UDCA and its conjugates by human cryopreserved hepatocytes, and more than half of the overall uptake involved a saturable component. Kinetic analyses revealed that the contribution of Na+-dependent and -independent pathways to the uptake of UDCA or TUDC was very similar, while the Na+-independent uptake of GUDC was predominant. These results suggest that UDCA and its conjugates are taken up by both multiple saturable transport systems and nonsaturable transport in human liver with different contributions. These results provide an explanation for the efficient hepatic clearance of UDCA and its conjugates in patients receiving UDCA therapy.

    Keywords: Ursodeoxycholate; organic anion transporting polypeptide; OATP; Na+-taurocholate cotransporting polypeptide (NTCP); hepatic uptake; human hepatocytes

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     University of Tokyo.

     University of California.

    *

     Corresponding author. Mailing address:  Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Tel:  +81-3-5841-4770. Fax:  +81-3-5841-4766. E-mail:  [email protected].

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