Developmental toxicity and toxicokinetics of two endothelin receptor antagonists in rats and rabbits

Embryo-fetal development studies with toxicokinetic evaluations were conduc ted in rats and rabbits after oral or intravenous administration of two end othelin 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) in travenously from days 6-17 postcoitus (pc). External and visceral fetal exa minations were performed at necropsy on day 21 pc. Maternal body weight and food consumption were decreased only at 300 mg/kg/day SB-217242. Embryolet hality was seen at 300 mg/kg/day SB-217242. Decreased fetal body weight occ urred 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 greater than or equal to 50 mg/kg/day SB-217242 and greater th an or equal to 10 mg/kg/day SB-209670. Craniofacial, great vessel, heart, a nd thyroid were the predominant malformations. In the rabbit studies, femal es were administered SB-217242 (0.01-50 mg/kg/day) orally or SE-209670 (0.0 1-25 mg/kg/day) intravenously from days 6-20 pc. There was no drug-related effect on maternal body weight or food consumption. Embryolethality was obs erved at 50 mg/kg/day of SB-217242. Dose-related increases in the mean perc entage of fetuses per litter with malformations were seen at greater than o r equal to 10 mg/kg/day SB-217242 and greater than or equal to 10 mg/kg/day SB-209670. The malformations were similar to those observed in the rat stu dies, except that craniofacial development was not altered by SB-209670. Th e malformations observed are consistent with the pattern of endothelin-1 ge ne expression described in mouse embryonic pharyngeal arches and heart, and with the craniofacial and cardiovascular malformations observed in endothe lin-1-deficient mice. Given the known role for endothelins in development, and concordant malformations in rats and rabbits observed in this study, te ratogenicity is likely to be a class effect of endothelin receptor antagoni sts. Teratology 59:51-59, 1999. (C) 1999 Wiley-Liss, Inc.