Related Experiment Video
Updated: Aug 22, 2025
Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
Published on: January 7, 2019
Liver enzyme delayed clearance in rat treated by CSF1 receptor specific antagonist Sotuletinib
François Pognan1, Chiara Buono2, Philippe Couttet1
1Novartis Institute for Biomedical Research, Basel, Switzerland.
Abstract:
Sotuletinib (BLZ945), a CSF1-R specific kinase inhibitor developed for the treatment of Amyotrophic Lateral Sclerosis, induced liver enzyme elevation in absence of hepatocellular lesions in preclinical rat and monkey studies. The monocytic cell family, including Kupffer cells, e.g., the liver-resident macrophages, are dependent upon CSF1 pathway activation for their survival, proliferation, and differentiation. Kupffer cells act as the main body compartment responsible for elimination of some blood-borne proteins, like ALT, AST, and few others. The depletion of Kupffer cells through CSF1 pathway inhibition has already been hypothesized as responsible for apparent liver enzyme elevation without detectable corresponding liver damage. However, a release of these biomarkers from unseen hepatic lesions or from other organs cannot be excluded. In order to eliminate a potential contribution of ALT elevation from an internal organ source, we injected recombinant his-Tagged ALT1 into rats pretreated with Sotuletinib. The elimination rate of the exogenous ALT1 was significantly lower in treated animals, demonstrating a delayed clearance independently of any potential organ lesions.
Insights
Sotuletinib treatment in rats caused elevated liver enzymes without liver damage. This occurred because the drug reduced Kupffer cells, which normally clear these enzymes, leading to slower clearance of introduced enzymes.
Area of Science:
- Pharmacology
- Hepatology
- Immunology
Background:
- Sotuletinib (BLZ945), a CSF1-R inhibitor for ALS, caused liver enzyme elevation in preclinical studies without hepatocellular lesions.
- Kupffer cells, liver-resident macrophages, depend on CSF1 for survival and are involved in eliminating liver enzymes like ALT and AST.
Purpose of the Study:
- To investigate the mechanism behind Sotuletinib-induced liver enzyme elevation.
- To determine if Kupffer cell depletion is the sole cause of elevated ALT/AST.
- To assess if Sotuletinib affects enzyme clearance independent of liver injury.
Main Methods:
- Pretreatment of rats with Sotuletinib.
- Intravenous injection of recombinant his-Tagged ALT1 into control and Sotuletinib-treated rats.
- Monitoring and comparison of exogenous ALT1 elimination rates between groups.
Main Results:
- Sotuletinib-treated rats exhibited a significantly lower elimination rate of exogenous ALT1 compared to controls.
- This demonstrates a delayed clearance of ALT1 in animals treated with Sotuletinib.
- The findings indicate impaired enzyme clearance independent of potential hepatic lesions.
Conclusions:
- Sotuletinib-induced liver enzyme elevation is partly due to impaired Kupffer cell function and subsequent reduced enzyme clearance.
- This mechanism explains elevated liver enzymes without detectable liver damage.
- CSF1-R inhibition impacts the pharmacokinetic profile of liver enzymes.
Related Concept Videos
01:09Hepatic Drug Clearance: Effect of Protein Binding
For low-extraction-ratio drugs that are less than 80% protein-bound, minor changes in protein binding...
01:23Nonlinear Pharmacokinetics: Dependence of Elimination Half-Life and Dose Clearance
A study on guinea pigs examined the...
01:14Hepatic Drug Clearance: Role of Transporters