@article {Li1751, author = {Xiuli Li and Kan Zhong and Zitao Guo and Dafang Zhong and Xiaoyan Chen}, title = {Fasiglifam (TAK-875) Inhibits Hepatobiliary Transporters: A Possible Factor Contributing to Fasiglifam-Induced Liver Injury}, volume = {43}, number = {11}, pages = {1751--1759}, year = {2015}, doi = {10.1124/dmd.115.064121}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Fasiglifam (TAK-875), a selective G-protein{\textendash}coupled receptor 40 agonist, was developed for the treatment of type 2 diabetes mellitus; however, its development was terminated in phase III clinical trials because of liver safety concerns. Our preliminary study indicated that intravenous administration of 100 mg/kg of TAK-875 increased the serum total bile acid concentration by 3 to 4 times and total bilirubin levels by 1.5 to 2.6 times in rats. In the present study, we examined the inhibitory effects of TAK-875 on hepatobiliary transporters to explore the mechanisms underlying its hepatotoxicity. TAK-875 decreased the biliary excretion index and the in vitro biliary clearance of d8-taurocholic acid in sandwich-cultured rat hepatocytes, suggesting that TAK-875 impaired biliary excretion of bile acids, possibly by inhibiting bile salt export pump (Bsep). TAK-875 inhibited the efflux transporter multidrug resistance-associated protein 2 (Mrp2) in rat hepatocytes using 5 (and 6)-carboxy-2',7'-dichlorofluorescein as a substrate. Inhibition of MRP2 was further confirmed by reduced transport of vinblastine in Madin-Darby canine kidney cells overexpressing MRP2 with IC50 values of 2.41 μM. TAK-875 also inhibited the major bile acid uptake transporter Na+/taurocholate cotransporting polypeptide (Ntcp), which transports d8-taurocholic acid into rat hepatocytes, with an IC50 value of 10.9 μM. TAK-875 significantly inhibited atorvastatin uptake in organic anion transporter protein (OATP) 1B1 and OATP1B3 cells with IC50 values of 2.28 and 3.98 μM, respectively. These results indicate that TAK-875 inhibited the efflux transporter MRP2/Mrp2 and uptake transporters Ntcp and OATP/Oatp, which may affect bile acid and bilirubin homeostasis, resulting in hyperbilirubinemia and cholestatic hepatotoxicity.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/43/11/1751}, eprint = {https://dmd.aspetjournals.org/content/43/11/1751.full.pdf}, journal = {Drug Metabolism and Disposition} }