Bile Acid Sequestration by Cholestyramine Mitigates FGFR4 Inhibition-Induced ALT Elevation
| Autor: | Terrilyn A. Richardson, Chi-Hse Teng, Audrey Fischer, Marianne Schwald, William Kluwe, Joerg Andreas Mahl, Robin Alec Fairhurst, Luigi Manenti, Francois Pognan, Armin Wolf, Gerd A. Kullak-Ublick, Mathilde Lienard, Jacqueline Kinyamu-Akunda, Elizabeth Skuba, Salah-Dine Chibout, Andreas Weiss, Kuno Wuersch, Philippe Couttet, Heiko Schadt, Diana Graus Porta, Corinne Emotte |
|---|---|
| Přispěvatelé: | University of Zurich, Kinyamu-Akunda, Jacqueline |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty medicine.drug_class Pyridines Cholestyramine Resin 610 Medicine & health Toxicology Cholesterol 7 alpha-hydroxylase Piperazines Bile Acids and Salts 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Dogs Internal medicine Toxicity Tests medicine Animals Receptor Fibroblast Growth Factor Type 4 Protein Kinase Inhibitors Cholestyramine biology Bile acid Dose-Response Relationship Drug 3005 Toxicology FGF19 Alanine Transaminase Toxicokinetics Dose–response relationship 030104 developmental biology Endocrinology Alanine transaminase chemistry Liver 10199 Clinic for Clinical Pharmacology and Toxicology 030220 oncology & carcinogenesis biology.protein Female Taurolithocholic acid Taurodeoxycholic acid medicine.drug |
| Zdroj: | Toxicological sciences : an official journal of the Society of Toxicology. 163(1) |
| ISSN: | 1096-0929 |
| Popis: | The FGF19- fibroblast growth factor receptor (FGFR4)-βKlotho (KLB) pathway plays an important role in the regulation of bile acid (BA) homeostasis. Aberrant activation of this pathway has been described in the development and progression of a subset of liver cancers including hepatocellular carcinoma, establishing FGFR4 as an attractive therapeutic target for such solid tumors. FGF401 is a highly selective FGFR4 kinase inhibitor being developed for hepatocellular carcinoma, currently in phase I/II clinical studies. In preclinical studies in mice and dogs, oral administration of FGF401 led to induction of Cyp7a1, elevation of its peripheral marker 7alpha-hydroxy-4-cholesten-3-one, increased BA pool size, decreased serum cholesterol and diarrhea in dogs. FGF401 was also associated with increases of serum aminotransferases, primarily alanine aminotransferase (ALT), in the absence of any observable adverse histopathological findings in the liver, or in any other organs. We hypothesized that the increase in ALT could be secondary to increased BAs and conducted an investigative study in dogs with FGF401 and coadministration of the BA sequestrant cholestyramine (CHO). CHO prevented and reversed FGF401-related increases in ALT in dogs in parallel to its ability to reduce BAs in the circulation. Correlation analysis showed that FGF401-mediated increases in ALT strongly correlated with increases in taurolithocholic acid and taurodeoxycholic acid, the major secondary BAs in dog plasma, indicating a mechanistic link between ALT elevation and changes in BA pool hydrophobicity. Thus, CHO may offer the potential to mitigate elevations in serum aminotransferases in human subjects that are caused by targeted FGFR4 inhibition and elevated intracellular BA levels. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|