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Developmental toxicity and toxicokinetics of two endothelin receptor antagonists in rats and rabbits
K A Treinen1, C Louden, M J Dennis
1Department of Safety Assessment, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Abstract:
Embryo-fetal development studies with toxicokinetic evaluations were conducted in rats and rabbits after oral or intravenous administration of two endothelin receptor antagonists. In the rat studies, females were administered SB-217242 (0.01-300 mg/kg/day) orally or SB-209670 (0.01-50 mg/kg/day) intravenously from days 6-17 postcoitus (pc). External and visceral fetal examinations were performed at necropsy on day 21 pc. Maternal body weight and food consumption were decreased only at 300 mg/kg/day SB-217242. Embryolethality was seen at 300 mg/kg/day SB-217242. Decreased fetal body weight occurred at 300 mg/kg/day SB-217242 and 50 mg/kg/day SB-209670. Dose-dependent increases in the mean percentage of fetuses per litter with malformations were seen at > or = 50 mg/kg/day SB-217242 and > or = 10 mg/kg/day SB-209670. Craniofacial, great vessel, heart, and thyroid were the predominant malformations. In the rabbit studies, females were administered SB-217242 (0.01-50 mg/kg/day) orally or SB-209670 (0.01-25 mg/kg/day) intravenously from days 6-20 pc. There was no drug-related effect on maternal body weight or food consumption. Embryolethality was observed at 50 mg/kg/day of SB-217242. Dose-related increases in the mean percentage of fetuses per litter with malformations were seen at > or = 10 mg/kg/day SB-217242 and > or = 10 mg/kg/day SB-209670. The malformations were similar to those observed in the rat studies, except that craniofacial development was not altered by SB-209670. The malformations observed are consistent with the pattern of endothelin-1 gene expression described in mouse embryonic pharyngeal arches and heart, and with the craniofacial and cardiovascular malformations observed in endothelin-1-deficient mice. Given the known role for endothelins in development, and concordant malformations in rats and rabbits observed in this study, teratogenicity is likely to be a class effect of endothelin receptor antagonists.
Insights
Endothelin receptor antagonists caused fetal malformations in rats and rabbits, suggesting teratogenicity is a class effect. These developmental toxicities, including embryolethality and birth defects, highlight risks associated with these compounds.
Area of Science:
- Toxicology
- Developmental Biology
- Pharmacology
Background:
- Endothelin receptor antagonists are investigated for therapeutic potential.
- Endothelins play a crucial role in embryonic development.
- Previous studies suggest potential risks of endothelin pathway modulation during gestation.
Purpose of the Study:
- To evaluate the embryo-fetal developmental toxicity of two endothelin receptor antagonists, SB-217242 and SB-209670.
- To assess toxicokinetic profiles following oral and intravenous administration in animal models.
- To determine if teratogenicity is a class effect of endothelin receptor antagonists.
Main Methods:
- Embryo-fetal development studies were conducted in pregnant rats and rabbits.
- Animals received oral or intravenous doses of SB-217242 or SB-209670 during critical gestation periods.
- Fetal examinations included external, visceral, and skeletal assessments; toxicokinetic evaluations were also performed.
Main Results:
- SB-217242 and SB-209670 induced dose-dependent malformations in rat and rabbit fetuses.
- Observed malformations included craniofacial, cardiovascular, and thyroid defects, consistent with endothelin-1 expression patterns.
- Embryolethality and decreased fetal body weight were noted at higher doses.
Conclusions:
- Teratogenicity is likely a class effect of endothelin receptor antagonists.
- These findings underscore the developmental risks associated with this class of drugs.
- Caution is advised when considering endothelin receptor antagonists during pregnancy.