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Research ArticleArticle

Fasiglifam (TAK-875) Inhibits Hepatobiliary Transporters: A Possible Factor Contributing to Fasiglifam-Induced Liver Injury

Xiuli Li, Kan Zhong, Zitao Guo, Dafang Zhong and Xiaoyan Chen
Drug Metabolism and Disposition November 2015, 43 (11) 1751-1759; DOI: https://doi.org/10.1124/dmd.115.064121
Xiuli Li
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
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Kan Zhong
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
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Zitao Guo
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
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Dafang Zhong
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
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Xiaoyan Chen
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
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Abstract

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.

Footnotes

    • Received March 3, 2015.
    • Accepted August 12, 2015.
  • Xiuli Li and Kan Zhong contributed equally to this work.

  • This work was supported by the National Natural Science Foundation of China [81173115 and 81173117].

  • dx.doi.org/10.1124/dmd.115.064121.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (11)
Drug Metabolism and Disposition
Vol. 43, Issue 11
1 Nov 2015
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Research ArticleArticle

TAK-875 Inhibits Hepatobiliary Transporters

Xiuli Li, Kan Zhong, Zitao Guo, Dafang Zhong and Xiaoyan Chen
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1751-1759; DOI: https://doi.org/10.1124/dmd.115.064121

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Research ArticleArticle

TAK-875 Inhibits Hepatobiliary Transporters

Xiuli Li, Kan Zhong, Zitao Guo, Dafang Zhong and Xiaoyan Chen
Drug Metabolism and Disposition November 1, 2015, 43 (11) 1751-1759; DOI: https://doi.org/10.1124/dmd.115.064121
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