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

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...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Katarzyna Bazydlo-Guzenda, Pawel Buda, Mateusz Mach, Jerzy Pieczykolan, Izabela Kozlowska, Michal Janiszewski, Ewa Drzazga, Jakub Dominowski, Hubert Ziolkowski, Maciej Wieczorek, Shayne Cox Gad
Formato: article
Lenguaje:EN
Publicado: Public Library of Science (PLoS) 2021
Materias:
R
Q
Acceso en línea:https://doaj.org/article/0bb5f2026cea4ecb8832d48ef5bc4190
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:0bb5f2026cea4ecb8832d48ef5bc4190
record_format dspace
spelling oai:doaj.org-article:0bb5f2026cea4ecb8832d48ef5bc41902021-12-02T20:08:04ZEvaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey.1932-620310.1371/journal.pone.0257477https://doaj.org/article/0bb5f2026cea4ecb8832d48ef5bc41902021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0257477https://doaj.org/toc/1932-6203GPR40 (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.Katarzyna Bazydlo-GuzendaPawel BudaMateusz MachJerzy PieczykolanIzabela KozlowskaMichal JaniszewskiEwa DrzazgaJakub DominowskiHubert ZiolkowskiMaciej WieczorekShayne Cox GadPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 9, p e0257477 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Katarzyna Bazydlo-Guzenda
Pawel Buda
Mateusz Mach
Jerzy Pieczykolan
Izabela Kozlowska
Michal Janiszewski
Ewa Drzazga
Jakub Dominowski
Hubert Ziolkowski
Maciej Wieczorek
Shayne Cox Gad
Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey.
description 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.
format article
author Katarzyna Bazydlo-Guzenda
Pawel Buda
Mateusz Mach
Jerzy Pieczykolan
Izabela Kozlowska
Michal Janiszewski
Ewa Drzazga
Jakub Dominowski
Hubert Ziolkowski
Maciej Wieczorek
Shayne Cox Gad
author_facet Katarzyna Bazydlo-Guzenda
Pawel Buda
Mateusz Mach
Jerzy Pieczykolan
Izabela Kozlowska
Michal Janiszewski
Ewa Drzazga
Jakub Dominowski
Hubert Ziolkowski
Maciej Wieczorek
Shayne Cox Gad
author_sort Katarzyna Bazydlo-Guzenda
title Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey.
title_short Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey.
title_full Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey.
title_fullStr Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey.
title_full_unstemmed Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey.
title_sort evaluation of the hepatotoxicity of the novel gpr40 (ffar1) agonist cpl207280 in the rat and monkey.
publisher Public Library of Science (PLoS)
publishDate 2021
url https://doaj.org/article/0bb5f2026cea4ecb8832d48ef5bc4190
work_keys_str_mv AT katarzynabazydloguzenda evaluationofthehepatotoxicityofthenovelgpr40ffar1agonistcpl207280intheratandmonkey
AT pawelbuda evaluationofthehepatotoxicityofthenovelgpr40ffar1agonistcpl207280intheratandmonkey
AT mateuszmach evaluationofthehepatotoxicityofthenovelgpr40ffar1agonistcpl207280intheratandmonkey
AT jerzypieczykolan evaluationofthehepatotoxicityofthenovelgpr40ffar1agonistcpl207280intheratandmonkey
AT izabelakozlowska evaluationofthehepatotoxicityofthenovelgpr40ffar1agonistcpl207280intheratandmonkey
AT michaljaniszewski evaluationofthehepatotoxicityofthenovelgpr40ffar1agonistcpl207280intheratandmonkey
AT ewadrzazga evaluationofthehepatotoxicityofthenovelgpr40ffar1agonistcpl207280intheratandmonkey
AT jakubdominowski evaluationofthehepatotoxicityofthenovelgpr40ffar1agonistcpl207280intheratandmonkey
AT hubertziolkowski evaluationofthehepatotoxicityofthenovelgpr40ffar1agonistcpl207280intheratandmonkey
AT maciejwieczorek evaluationofthehepatotoxicityofthenovelgpr40ffar1agonistcpl207280intheratandmonkey
AT shaynecoxgad evaluationofthehepatotoxicityofthenovelgpr40ffar1agonistcpl207280intheratandmonkey
_version_ 1718375224033935360