Characterization of ursodeoxycholic and norursodeoxycholic acid as substrates of the hepatic uptake transporters OATP1B1, OATP1B3, OATP2B1 and NTCP

Basic & Clinical Pharmacology & Toxicology
J KönigM F Fromm

Abstract

Ursodeoxycholic acid (UDCA) is the only approved treatment for primary biliary cirrhosis, and norursodeoxycholic acid (norUDCA) 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 norUDCA into hepatocytes is believed to be a prerequisite for subsequent metabolism and therapeutic action. However, the molecular determinants of hepatocellular uptake of UDCA and norUDCA are poorly understood. We therefore investigated whether UDCA and norUDCA 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]norUDCA 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 norUDCA uptake were at maximum 1.23 and 1.49, respectively. Uptake of UDCA was sign...Continue Reading

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Citations

Sep 19, 2015·Clinical and Experimental Pharmacology & Physiology·Miao HuBrian Tomlinson
Dec 3, 2014·International Journal of Pharmaceutics·Zhongqi DongJames E Polli
Mar 14, 2013·Basic & Clinical Pharmacology & Toxicology·Victoria C ZiesenitzGerd Mikus
Mar 3, 2018·Basic & Clinical Pharmacology & Toxicology·Yu ChenChunhua Xia
Jul 7, 2018·Biopharmaceutics & Drug Disposition·Yanming XiaJunsong Li
Mar 1, 2018·Pharmacological Reviews·Fabian MüllerMartin F Fromm
May 6, 2021·Photochemistry and Photobiology·Dongping MaJames J Cali

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