ArticleToxicological sciences : an official journal of the Society of Toxicology2017
Fasiglifam (TAK-875) Alters Bile Acid Homeostasis in Rats and Dogs: A Potential Cause of Drug Induced Liver Injury.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 46 citations in OpenAlex.
- Phase I study of PF‐04895162, a Kv7 channel opener, reveals unexpected hepatotoxicity in healthy subjects, but not rats or monkeys: clinical evidence of disrupted bile acid homeostasis.Pharmacology research & perspectives · 2019Trial
- Liver Safety of Fasiglifam (TAK-875) in Patients with Type 2 Diabetes: Review of the Global Clinical Trial Experience.Drug safety · 2018Trial
- Human-relevant mechanisms and risk factors for TAK-875-Induced liver injury identified via a gene pathway-based approach in Collaborative Cross mice.Toxicology · 2021Article
- GPR40 receptor agonist TAK-875 improves cognitive deficits and reduces β-amyloid production in APPswe/PS1dE9 mice.Psychopharmacology · 2021Article
- Novel therapies with precision mechanisms for type 2 diabetes mellitus.Nature reviews. Endocrinology · 2021Review
- Targeting lipid GPCRs to treat type 2 diabetes mellitus - progress and challenges.Nature reviews. Endocrinology · 2021Review
- Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey.PloS one · 2021Article
- Prospect ofFrontiers in toxicology · 2021Review
- The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates.Frontiers in pharmacology · 2021Review
- Polygenic architecture informs potential vulnerability to drug-induced liver injury.Nature medicine · 2020Article
- Quantitative Systems Toxicology Analysis of In Vitro Mechanistic Assays Reveals Importance of Bile Acid Accumulation and Mitochondrial Dysfunction in TAK-875-Induced Liver Injury.Toxicological sciences : an official journal of the Society of Toxicology · 2019Article
- Quantitative translational modeling to facilitate preclinical to clinical efficacy & toxicity translation in oncology.Future science OA · 2018Review
- Evaluation of the Pharmacokinetics and Safety of a Single Oral Dose of Fasiglifam in Subjects with Mild or Moderate Hepatic Impairment.Drugs in R&D · 2018Article
- Dissecting the Physiology and Pathophysiology of Glucagon-Like Peptide-1.Frontiers in endocrinology · 2018Review
- SAR Studies of Indole-5-propanoic Acid Derivatives To Develop Novel GPR40 Agonists.ACS medicinal chemistry letters · 2017Article
- FFA4/GPR120: Pharmacology and Therapeutic Opportunities.Trends in pharmacological sciences · 2017Review
- Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury.Archives of toxicology · 2017Article
- Pharmacokinetic and toxicodynamic concepts in idiosyncratic, drug-induced liver injury.Expert opinion on drug metabolism & toxicologyArticle
Corrections and comments
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Authors and funding
16 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.