Developmental toxicity of alprostadil in rats after subcutaneous administration or intravenous infusion.
Timed-pregnant Upj:TUC(SD)spf (Sprague-Dawley) rats were dosed with alprostadil (prostaglandin E1), either subcutaneously on Days 6-15 of gestation at 0.0, 0.5, 1.0, or 2.0 mg/kg/day or by iv infusion into the jugular vein (24 hr/day) on Days 7-15 at 0.0, 0.5, 1.0, 2.0, 4.0, or 6.0 mg/kg/day. Maternal toxicity was observed in all dams receiving alprostadil subcutaneously, the severity of which increased in a dose-related manner. Toxicity also was evident in the offspring in the 2.0 mg/kg/day group as evidenced by a significant increase in the percentage of resorptions and a significant decrease in the percentage of live fetuses. Mean fetal weight was significantly depressed in all three alprostadil-treated groups and several skeletal and visceral variations were significantly higher in the 1.0 and 2.0 mg/kg/day groups than in the vehicle control group; in addition, there were two instances of significantly increased frequencies of skeletal variations in the 0.5 mg/kg/day group. Gross, visceral, and skeletal malformations were significantly increased in the high-dose group. During iv infusion of alprostadil more than 50% of the dams in the 6.0 mg/kg/day group died and there was one death in the 4.0 mg/kg/day group. Significant decreases in maternal weight gain between Days 7 and 11 of gestation were observed at doses of 1.0 mg/kg/day and above. However, continuous iv infusion of this prostaglandin, at dosages which were not severely toxic to the dams, was judged not to be teratogenic or otherwise embryotoxic in rats. The increase in uterine contractions, observed at 1.0 and 2.0 mg/kg after sc administration to rats implanted with chronic uterine microballoons, was consistent with the hypothesis that the developmental toxicity observed after bolus sc administration was the consequence of decreased blood flow in the uterus and/or placenta and/or embryos.
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Reproductive and Development Toxicology, Upjohn Company, Kalamazoo, Michigan 49001.
Morris
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Weeks
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D000014:Abnormalities, Drug-Induced / Q000209:etiology / Q000503:physiopathology*; D000042:Absorption; D000527:Alprostadil / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D003333:Coronaviridae Infections / Q000503:physiopathology; D004334:Drug Administration Schedule; D005260:Female; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D009999:Ossification, Heterotopic / Q000139:chemically induced; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D014590:Uterine Contraction / Q000187:drug effects
D000527:Alprostadil