Fasiglifam (TAK-875) Inhibits Hepatobiliary Transporters: A Possible Factor Contributing to Fasiglifam-Induced Liver Injury.
Fasiglifam (TAK-875), a selective G-protein-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.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Xiuli
X
Li
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Kan
K
Zhong
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Zitao
Z
Guo
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Dafang
D
Zhong
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China xychen@simm.ac.cn.
Xiaoyan
X
Chen
D000818:Animals; D001572:Benzofurans / Q000378:metabolism / Q000494:pharmacology*; D001659:Biliary Tract / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000378:metabolism / Q000494:pharmacology*; D027981:Symporters / Q000037:antagonists & inhibitors / Q000378:metabolism
D001572:Benzofurans; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D013450:Sulfones; D027981:Symporters; C000715087:ABCC2 protein, human; C557331:TAK-875; C071908:sodium-bile acid cotransporter