Developmental toxicity and toxicokinetics of two endothelin receptor antagonists in rats and rabbits.
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.
Treinen
K A
KA
Department of Safety Assessment, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Louden
C
C
Dennis
M J
MJ
Wier
P J
PJ
D000014:Abnormalities, Drug-Induced; D000818:Animals; D019540:Area Under Curve; D002264:Carboxylic Acids / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D065128:Endothelin Receptor Antagonists; D005260:Female; D005333:Fetus / Q000187:drug effects; D007189:Indans / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000493:pharmacokinetics / Q000633:toxicity