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Characterization of Ursodeoxycholic and Norursodeoxycholic Acid as Substrates of the Hepatic Uptake Transporters OATP 1B1, OATP 1B3, OATP 2B1 and NTCP
Author(s) -
König Jörg,
Klatt Sabine,
Dilger Karin,
Fromm Martin F.
Publication year - 2012
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2012.00865.x
Subject(s) - ursodeoxycholic acid , transporter , chemistry , hek 293 cells , organic anion transporting polypeptide , organic anion transporter 1 , bile salt export pump , pharmacology , bile acid , transfection , biochemistry , biology , receptor , gene
Ursodeoxycholic acid ( UDCA ) is the only approved treatment for primary biliary cirrhosis, and norursodeoxycholic acid ( nor UDCA ) is currently tested in clinical trials for future treatment of primary sclerosing cholangitis because of beneficial effects in cholestatic Mdr2 knock‐out mice. Uptake of UDCA and nor UDCA into hepatocytes is believed to be a prerequisite for subsequent metabolism and therapeutic action. However, the molecular determinants of hepatocellular uptake of UDCA and nor UDCA are poorly understood. We therefore investigated whether UDCA and nor UDCA are substrates of the hepatic uptake transporters OATP1B1 , OATP1B3 , OATP2B1 and Na + ‐taurocholate co‐transporting polypeptide ( NTCP ), which are localized in the basolateral membrane of hepatocytes. Uptake of [ 3 H] UDCA and [ 14 C] nor UDCA into Human embryonic kidney ( HEK ) cells stably expressing OATP1B1 , OATP1B3 , OATP2B1 or NTCP was investigated and compared with uptake into vector control cells. Uptake ratios were calculated by dividing uptake into transporter‐transfected cells by uptake into respective control cells. Uptake ratios of OATP1B1 ‐, OATP1B3 ‐ and OATP2B1 ‐mediated UDCA and nor UDCA uptake were at maximum 1.23 and 1.49, respectively. Uptake of UDCA was significantly higher into HEK ‐ NTCP cells only at the lowest tested concentration (1 μM, p < 0.001) compared with the control cells with an uptake ratio of 1.34‐fold. Nor UDCA was not significantly transported by NTCP . The low uptake rates suggest that OATP1B1 , OATP1B3 , OATP2B1 and NTCP are not relevant for hepatocellular uptake and effects of UDCA and nor UDCA in human beings.