Nonclinical Safety Assessment of the Histone Deacetylase Inhibitor Vorinostat
Autor: | Victoria M. Richon, Thomas A. Miller, Janet S. Kerr, Armando Lagrutta, Michael J. Armstrong, Paul A. Andrews, Sheila M. Galloway |
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Rok vydání: | 2009 |
Předmět: |
Salmonella typhimurium
medicine.drug_class Drug Evaluation Preclinical CHO Cells Biology Pharmacology Hydroxamic Acids Toxicology medicine.disease_cause Histone Deacetylases Ames test Eating Mice Cricetulus Dogs In vivo Cricetinae Toxicity Tests Weight Loss medicine Animals Humans Stomach Ulcer Enzyme Inhibitors Vorinostat Micronuclei Chromosome-Defective Blood Cells Micronucleus Tests Body Weight Histone deacetylase inhibitor DNA Rats Gastric Mucosa Micronucleus test Toxicity Histone deacetylase Genotoxicity medicine.drug |
Zdroj: | International Journal of Toxicology. 29:3-19 |
ISSN: | 1092-874X 1091-5818 |
Popis: | Vorinostat (SAHA, Zolinza), a histone deacetylase inhibitor, is assessed in nonclinical studies to support its approval for cutaneous T-cell lymphoma. Vorinostat is weakly mutagenic in the Ames assay; is clastogenic in rodent (ie, CHO) cells but not in normal human lymphocytes; and is weakly positive in an in vivo mouse micronucleus assay. No effects are observed on potassium ion currents in the hERG assay up to 300 microM (safety margin approximately 300-fold the approximately 1 microM serum concentration associated with the 400 mg/d maximum recommended human dose. No rat respiratory or central nervous system effects are found at 150 mg/kg (2-fold maximum recommended human dose). No cardiovascular effects, including effects on QTc interval, are observed after a single oral dose (150 mg/kg) in dogs. Vorinostat is orally dosed daily in rats (controls, 20, 50, or 150 mg/kg/d) and dogs (controls, 60, 80, or 100/125/160 mg/kg/d) for 26 weeks with a 4-week recovery. Rat vorinostat-related adverse findings are decreased food consumption, weight loss, and hematologic changes; a no observed adverse effects level is not established. In dogs, adverse effects are primarily gastrointestinal; the no observed adverse effects level is 60 mg/kg/d (approximately 6-fold maximum recommended human dose). Toxicities are reversible and can be monitored in the clinic. |
Databáze: | OpenAIRE |
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