Assessment of developmental toxicity of vorinostat, a histone deacetylase inhibitor, in Sprague-Dawley rats and Dutch Belted rabbits.
Birth Defects Res B Dev Reprod Toxicol
; 80(1): 57-68, 2007 Feb.
Article
in En
| MEDLINE
| ID: mdl-17294457
ABSTRACT
BACKGROUND:
The developmental toxicity potential of vorinostat (suberoylanilide hydroxamic acid [SAHA], ZOLINZA), a potent inhibitor of histone deacetylase (HDAC), was assessed in Sprague-Dawley rats and Dutch Belted rabbits. HDAC inhibitors have been shown to mediate the regulation of gene expression, induce cell growth, cell differentiation, and apoptosis of tumor cells. Range-finding studies established oral dose levels of 5, 15, or 50 mg/kg/day and 20, 50, or 150 mg/kg/day in rats and rabbits, respectively.METHODS:
Animals were dosed on Gestation Days 6-20 or 7-20, respectively, with litter/fetal parameters evaluated on GD 21 and 28, respectively. Separate studies evaluated toxicokinetic parameters at the mid- and high-dose levels.RESULTS:
There was no maternal toxicity observed at the highest dose levels; however, hematology and serum biochemistry changes were characterized in the range-finding studies. Vorinostat did not induce morphological malformations in either rat or rabbit fetuses. In rats, drug-related developmental toxicity was observed only in the high-dose group and consisted of markedly decreased fetal weight and increases in fetuses with a limited number of skeletal variations. In rabbits, drug-related developmental toxicity was also observed only in the high-dose group and consisted of slightly decreased fetal weight and increases in fetuses with a short 13th rib and incomplete ossification of metacarpals. Maternal exposures to vorinostat based on AUC and Cmax values were comparable at the high-dose levels of both species. Rabbits tolerated higher dosages probably due to more extensive metabolism. Maternal concentrations of vorinostat were approximately 1,000-fold above the known in vitro HDAC inhibitory concentration.CONCLUSIONS:
Review of previous work with valproic acid, another HDAC inhibitor, suggest that the developmental toxicity profiles of these 2 compounds are not the result of HDAC inhibition but involve other mechanisms.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Abnormalities, Drug-Induced
/
Enzyme Inhibitors
/
Histone Deacetylase Inhibitors
/
Fetus
/
Hydroxamic Acids
Limits:
Animals
/
Pregnancy
Language:
En
Journal:
Birth Defects Res B Dev Reprod Toxicol
Journal subject:
TERATOLOGIA
/
TOXICOLOGIA
Year:
2007
Document type:
Article
Affiliation country:
United States