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Published on: March 23, 2013
Metabolic changes in rats after intragastric administration of MGCD0103 (Mocetinostat), a HDAC class I inhibitor
Qingwei Zhang1, Haiya Wu2, Congcong Wen3
1Shanghai Institute of Pharmaceutical Industry Shanghai 200437, China.
Abstract:
MGCD0103, an isotype-selective HDACi, has been clinically evaluated for the treatment of hematologic malignancies and advanced solid tumors, alone and in combination with standard-of-care agents. In this study, we developed a serum metabolomic method based on gas chromatography-mass spectrometry (GC-MS) to evaluate the effect of intragastric administration of MGCD0103 on rats. The MGCD0103 group rats were given 20, 40, 80 mg/kg of MGCD0103 by intragastric administration each day for 7 days. Pattern recognition analysis, including both principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA) revealed that intragastric administration of MGCD0103 induced metabolic perturbations. As compared to the control group, the levels of L-alanine, L-isoleucine, and L-leucine of MGCD0103 group decreased. The results indicate that metabolomic methods based on GC-MS may be useful to elucidate side effect of MGCD0103 through the exploration of biomarkers (L-alanine, L-isoleucine, and L-leucine). According to the pathological changes of liver at difference dosage, MGCD0103 is hepatotoxic and its toxity is dose-dependent.
Insights
This study used gas chromatography-mass spectrometry (GC-MS) to analyze the effects of MGCD0103 in rats. MGCD0103 treatment altered metabolic profiles and indicated potential liver toxicity, with effects being dose-dependent.
Area of Science:
- Pharmacology
- Toxicology
- Metabolomics
Background:
- MGCD0103 is an isotype-selective histone deacetylase inhibitor (HDACi) investigated for hematologic malignancies and solid tumors.
- Understanding the drug's metabolic impact and potential toxicities is crucial for its clinical application.
Purpose of the Study:
- To develop and apply a serum metabolomic method using GC-MS to assess the effects of MGCD0103 in rats.
- To identify potential biomarkers for MGCD0103's side effects and evaluate its hepatotoxicity.
Main Methods:
- Rats received daily intragastric administration of MGCD0103 (20, 40, 80 mg/kg) for 7 days.
- Serum samples were analyzed using gas chromatography-mass spectrometry (GC-MS).
- Pattern recognition analyses (PCA, PLS-DA) were employed to identify metabolic perturbations.
Main Results:
- MGCD0103 administration induced significant metabolic changes in rat serum.
- Levels of L-alanine, L-isoleucine, and L-leucine were decreased in the MGCD0103-treated groups compared to controls.
- Pathological examination revealed dose-dependent hepatotoxicity associated with MGCD0103 treatment.
Conclusions:
- GC-MS-based metabolomics can identify metabolic perturbations and potential biomarkers (L-alanine, L-isoleucine, L-leucine) for MGCD0103's side effects.
- MGCD0103 exhibits dose-dependent hepatotoxicity in rats.
- These findings contribute to understanding MGCD0103's safety profile.
