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

Ackerson, Timothy; Amberg, Alexander; Atzrodt, Jens; Arabeyre, Catherine; Defossa, Elisabeth; M, Dorau; Dudda, Angela; Dwyer, Jacquelyn; Holla, Wolfgang; Kissner, Thomas; Kohlmann, Markus; Kürzel, Ulrich; Pánczél, József; Rajanna, Shibani; Riedel, Jens; Schmidt, Friedemann; Wäse, Kerstin; Weitz, Dietmar; Derdau, Volker

doi:10.1002/jbt.22345

Cited by 21 publications

(12 citation statements)

References 56 publications

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“…In the viability study, TAK-875 showed an IC 50 of approximately 50 μM, which was in line with the values reported in initial studies detailing TAK-875 toxicity ( Fig 1 ) [ 25 ]. This was also in agreement with a more recent study by others who reported IC 50 values of 68 and 56 μM when the time of incubation was 24 and 48 h, respectively [ 45 ]. Authors underscored that the longer hepatocytes were incubated with the compound, the more sensitive they become to toxicity of the compound.…”

Section: Discussionsupporting

confidence: 93%

“…In contrast, TAK-875 impaired mitochondrial function and caused DNA damage. TAK-875 also reduced glutathione content in the cells, and even though it was reported elsewhere of no account for TAK-875 toxicity, it might still underlie the observed elevated oxidative stress ( Table 1 ) [ 45 ]. Regarding the deleterious effects of the parent molecule, it has been proposed that glucuronide (TAK-875-Glu), one of the main metabolites of TAK-875, might accumulate aside TAK-875 in the liver, thus causing additional injuries.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey

et al. 2021

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GPR40 (FFAR1) is a promising target for the managing type 2 diabetes (T2D). The most advanced GPR40 agonist TAK-875 exhibited satisfactory glucose-lowering effects in phase II and III studies. However, the phase III studies of TAK-875 revealed drug-induced liver injury (DILI). It is unknown whether DILI is a consequence of a specific GPR40 agonist or is an inherent feature of all GPR40 agonists. CPL207280 is a novel GPR40 agonist that improves diabetes in Zucker Diabetic Fatty (ZDF) rats, Goto Kakizaki (GK) rats and db/db mice. In this report, the DILI-related toxicity of CPL207280 was compared directly with that of TAK-875. In vitro studies evaluating hepatic biliary transporter inhibition, mitochondrial function, and metabolic profiling were performed in hepatocytes from different species. The long term toxicity of CPL207280 was studied in vivo in rats and monkeys. Activity of CPL207280 was one order of magnitude lesser than that of TAK-875 for the inhibition of bile acid transporters. CPL207280 had a negligible effect on the hepatic mitochondria. In contrast to TAK-875, which was metabolized through toxic glucuronidation, CPL207280 was metabolized mainly through oxidation. No deleterious hepatic effects were observed in chronically treated healthy and diabetic animals. The study presents promising data on the feasibility of creating a liver-safe GPR40 agonist. Additionally, it can be concluded that DILI is not a hallmark of GPR40 agonists; it is linked to the intrinsic properties of an individual agonist.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey

et al. 2021

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“…For example, ezetimibe-G, a substrate of OATPs and MRP2, is also a strong inhibitor of OATPs (half maximal inhibitory concentration (IC 50 ) <0.5 µM) and can inhibit BCRP, MRP2 and MRP3 ( Oswald et al, 2008 ; de Waart et al, 2009 ). Another drug conjugate with strong inhibition potential for both OATP1Bs and MRPs is fasiglifam-G, which has IC 50 values ≤1 µM for these transporters ( Otieno et al, 2018 ; Ackerson et al, 2019 ). Raloxifene-4′-G and raloxifene-6,4′-di-G appear able to inhibit all of the major hepatic drug transporters with IC 50 values <10 µM, but interpretation warrants caution as values for the efflux transporters are based on changes in ATPase activity and not inhibition of transport ( Trdan Lušin et al, 2012a ; 2012b ).…”

Section: Conjugates As Inhibitors Of Transportersmentioning

confidence: 99%

The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates

et al. 2022

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Glucuronidation and sulfation are the most typical phase II metabolic reactions of drugs. The resulting glucuronide and sulfate conjugates are generally considered inactive and safe. They may, however, be the most prominent drug-related material in the circulation and excreta of humans. The glucuronide and sulfate metabolites of drugs typically have limited cell membrane permeability and subsequently, their distribution and excretion from the human body requires transport proteins. Uptake transporters, such as organic anion transporters (OATs and OATPs), mediate the uptake of conjugates into the liver and kidney, while efflux transporters, such as multidrug resistance proteins (MRPs) and breast cancer resistance protein (BCRP), mediate expulsion of conjugates into bile, urine and the intestinal lumen. Understanding the active transport of conjugated drug metabolites is important for predicting the fate of a drug in the body and its safety and efficacy. The aim of this review is to compile the understanding of transporter-mediated disposition of phase II conjugates. We review the literature on hepatic, intestinal and renal uptake transporters participating in the transport of glucuronide and sulfate metabolites of drugs, other xenobiotics and endobiotics. In addition, we provide an update on the involvement of efflux transporters in the disposition of glucuronide and sulfate metabolites. Finally, we discuss the interplay between uptake and efflux transport in the intestine, liver and kidneys as well as the role of transporters in glucuronide and sulfate conjugate toxicity, drug interactions, pharmacogenetics and species differences.

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“…In addition, TAK-875 and zamifenacin were reported to be metabolized by CYPs. 25,26 The toxicity of ADX-10059 in HepG2 cells increased under galactose culture condition (Fig. 5), and that of TC-Hep cells was the same as that of HepG2 cells (Fig.…”

Section: Evaluation Of Discontinued Compounds Due To Liver Injurymentioning

confidence: 88%

Evaluation of Parent- and Metabolite-Induced Mitochondrial Toxicities Using CYP-Introduced HepG2 cells

Takemura¹,

Gong²,

Sato³

et al. 2021

Journal of Pharmaceutical Sciences

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Mitochondrial toxicity is an important factor to predict drug-induced liver injury (DILI). Previous studies have focused predominantly on mitochondrial toxicities due to parent forms, and no study has adequately evaluated metabolite-induced mitochondrial toxicity. Moreover, previous studies have used HepG2 cells, which lack many cytochrome P450 (CYP) genes. To overcome this problem, CYP-introduced HepG2 cells were constructed using several gene transfer technologies, including adenoviruses and plasmids. However, these methods only led to a transient expression of CYP genes. In the present study, usefulness of four CYPs introduced-HepG2 (TC-Hep) cells previously constructed through mammalian artificial chromosome technology were examined, especially from the perspective of mitochondrial toxicity. First, we evaluated the effects of known compounds, such as rotenone and flutamide, on mitochondrial toxicity and cell death in TC-Hep cells cultured in galactose conditions. Expectedly, rotenone-induced cell death ameliorated because rotenone was metabolized by CYPs into inactive form(s) and flutamide-induced cell death increased in TC-Hep cells. Second, we evaluated five compounds that caused liver injury in clinical phase and were discontinued during pharmaceutical development. The present in vitro tool suggested that three of the five compounds caused metabolite-induced mitochondrial toxicities. In conclusion, the present in vitro tool could easily and inexpensively detect metabolite-induced mitochondrial toxicity; hence, it can be useful for predicting DILI in preclinical phase.

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

Cited by 21 publications

References 56 publications

Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey

Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey

The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates

Evaluation of Parent- and Metabolite-Induced Mitochondrial Toxicities Using CYP-Introduced HepG2 cells

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