Fasiglifam (TAK-875), a selective G-protein-coupled receptor 40 agonist, was developed for the treatment of type 2 diabetes mellitus.However, its clinical development was terminated in phase Ⅲ clinical trials due to liver safety concerns.Our preliminary study indicated intravenous administration of 100 mg/kg of TAK-875 increased the serum total bile acid concentration by 2.2 times in rats.In the present study, we examined the inhibitory effects of TAK-875 on hepatobiliary transporters to determine the mechanisms underlying its hepatotoxicity.TAK-875 decreased the biliary excretion index and the in vitro biliary clearance of d8-taurocholic acid (d8-TCA) as a probe for bile acids transport 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 muhidrug resistance-associated protein 2 (Mrp2) in rat hepatocytes using 5 (and 6)-carboxy-2, 7-dichlorofluorescein as a substrate.