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

Li, Xiuli; Zhong, Ke; Guo, Zitao; Zhong, Dafang; Chen, Xiaoyan

doi:10.1124/dmd.115.064121

Cited by 78 publications

(61 citation statements)

References 40 publications

(39 reference statements)

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“…We also found that FFAR1, which codes for a GPCR that is activated by long chain fatty acids, is highly expressed in human and mouse islets. FFAR1 agonists have been considered as novel therapies for T2D, but the development of a promising candidate, TAK-87525, has been discontinued because of adverse effects on the liver26.…”

Section: Discussionmentioning

confidence: 99%

A comparative analysis of human and mouse islet G-protein coupled receptor expression

Amisten

Atanes

Hawkes

et al. 2017

Sci Rep

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G-protein coupled receptors (GPCRs) are essential for islet function, but most studies use rodent islets due to limited human islet availability. We have systematically compared the GPCR mRNA expression in human and mouse islets to determine to what extent mouse islets can be used as surrogates for human islets to study islet GPCR function, and we have identified species-specific expression of several GPCRs. The A3 receptor (ADORA3) was expressed only in mouse islets and the A3 agonist MRS 5698 inhibited glucose-induced insulin secretion from mouse islets, with no effect on human islets. Similarly, mRNAs encoding the galanin receptors GAL1 (GALR1), GAL2 (GALR2) and GAL3 GALR3) were abundantly expressed in mouse islets but present only at low levels in human islets, so that it reads (GALR3) and galanin inhibited insulin secretion only from mouse islets. Conversely, the sst1 receptor (SSTR1) was abundant only in human islets and its selective activation by CH 275 inhibited insulin secretion from human islets, with no effect on mouse islets. Our comprehensive human and mouse islet GPCR atlas has demonstrated that species differences do exist in islet GPCR expression and function, which are likely to impact on the translatability of mouse studies to the human context.

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Section: Discussionmentioning

confidence: 99%

A comparative analysis of human and mouse islet G-protein coupled receptor expression

Amisten

Atanes

Hawkes

et al. 2017

Sci Rep

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“…TAK-875 and TAK-875-Glu inhibit multiple human BA transporters at similar low micromolar concentrations (Figure 2a). Similarly, TAK-875 was shown to be an inhibitor of multiple rat hepatobilliary transporters (Li et al , 2015). Taken together, the effects on serum TBA appear to be a direct result of BA transporter inhibition.…”

Section: Discussionmentioning

confidence: 99%

Fasiglifam (TAK-875) alters bile acid homeostasis in rats and dogs: a potential cause of drug induced liver injury

et al. 2017

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Fasiglifam (TAK-875), a Free Fatty Acid Receptor 1 (FFAR1) agonist in development for the treatment of type 2 diabetes, was voluntarily terminated in phase 3 due to adverse liver effects. A mechanistic investigation described in this manuscript focused on the inhibition of bile acid (BA) transporters as a driver of the liver findings. TAK-875 was an in vitro inhibitor of multiple influx (NTCP and OATPs) and efflux (BSEP and MRPs) hepatobiliary BA transporters at micromolar concentrations. Repeat dose studies determined that TAK-875 caused a dose-dependent increase in serum total BA in rats and dogs. Additionally, there were dose-dependent increases in both unconjugated and conjugated individual BAs in both species. Rats had an increase in serum markers of liver injury without correlative microscopic signs of tissue damage. Two of 6 dogs that received the highest dose of TAK-875 developed liver injury with clinical pathology changes, and by microscopic analysis had portal granulomatous inflammation with neutrophils around a crystalline deposition. The BA composition of dog bile also significantly changed in a dose-dependent manner following TAK-875 administration. At the highest dose, levels of taurocholic acid were 50% greater than in controls with a corresponding 50% decrease in taurochenodeoxycholic acid. Transporter inhibition by TAK-875 may cause liver injury in dogs through altered bile BA composition characteristics, as evidenced by crystalline deposition, likely composed of test article, in the bile duct. In conclusion, a combination of in vitro and in vivo evidence suggests that BA transporter inhibition could contribute to TAK-875-mediated liver injury in dogs.

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“…However, as FFAR1 is not significantly expressed in the liver probably the toxic effect is not connected with the function of FFAR1 itself . Li et al suggest that TAK875 1 impairs biliary excretion of bile acid by inhibition of several hepatobiliary transporters, such as multidrug resistance‐associated protein 2 (MRP2), NTCP, organic anion‐transporting polypeptide (OATP), and BSEP, which was demonstrated in vitro with rat hepatocyte cultures or recombinant cell lines. As a consequence of the BSEP inhibition, TAK875 1 may lead to bile acid accumulation in human hepatocytes increasing the likelihood for cholestatic hepatotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic investigations of the liver toxicity of the free fatty acid receptor 1 agonist fasiglifam (TAK875) and its primary metabolites

Ackerson

Amberg

Atzrodt

et al. 2019

J Biochem & Molecular Tox

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For fasiglifam (TAK875) and its metabolites the substance‐specific mechanisms of liver toxicity were studied. Metabolism studies were run to identify a putatively reactive acyl glucuronide metabolite. In vitro cytotoxicity and caspase 3/7 activation were assessed in primary human and dog hepatocytes in 2D and 3D cell culture. Involvement of glutathione (GSH) detoxication system in mediating cytotoxicity was determined by assessing potentiation of cytotoxicity in a GSH depleted in vitro system. In addition, potential mitochondrial liabilities of the compounds were assessed in a whole‐cell mitochondrial functional assay. Fasiglifam showed moderate cytotoxicity in human primary hepatocytes in the classical 2D cytotoxicity assays and also in the complex 3D human liver microtissue (hLiMT) after short‐term treatment (24 hours or 48 hours) with TC50 values of 56 to 68 µM (adenosine triphosphate endpoint). The long‐term treatment for 14 days in the hLiMT resulted in a slight TC50 shift over time of 2.7/3.6 fold lower vs 24‐hour treatment indicating possibly a higher risk for cytotoxicity during long‐term treatment. Cellular GSH depletion and impairment of mitochondrial function by TAK875 and its metabolites evaluated by Seahorse assay could not be found being involved in DILI reported for TAK875. The acyl glucuronide metabolites of TAK875 have been finally identified to be the dominant reason for liver toxicity.

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

Cited by 78 publications

References 40 publications

A comparative analysis of human and mouse islet G-protein coupled receptor expression

A comparative analysis of human and mouse islet G-protein coupled receptor expression

Fasiglifam (TAK-875) alters bile acid homeostasis in rats and dogs: a potential cause of drug induced liver injury

Mechanistic investigations of the liver toxicity of the free fatty acid receptor 1 agonist fasiglifam (TAK875) and its primary metabolites

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