Preclinical safety evaluation of 15[S]15-methyl prostaglandin F2alpha : reproduction and teratology.

The abortifacient 15[S]15-methyl prostaglandin F2alpha, designated PGF2alpha (M), was tested in pregnant rats and rabbits for purposes of preclinical safety evaluation. The material tested was the tromethamine salt of PGF2alpha with the generic name, carboprost tromethamine. Doses of 0.25, 0.50, and 1 mg/kg given by subcutaneous injection to male and female rats for 3 or 6 consecutive days before mating did not have an adverse effect on reproduction. The principal finding in rat and rabbit teratology studies was that PGF2alpha (M) had a high order of embryolethality regardless of when it was administered. Rabbits were more sensitive than were rats and PGF2alpha (M) interfered with nidation or early embryonic development when given during the second week of gestation. The largest dose of PGF2alpha (M) that allowed some fetuses to survive was 0.25 mg/kg for rats and 0.005 mg/kg for rabbits when given by subcutaneous injection for 3 consecutive days at some point during organogenesis. Fetuses from rabbits given the doses of 0.0025 and 0.005 mg/kg were normal. There were a variety of skeletal anomalies (mostly of ribs and thoracic vertebrae) in fetuses from rats given, by subcutaneous injection, doses of PGF2alpha (M) ranging from 0.25 to 0.05 mg/kg for 3 consecutive days at some point during organogenesis. Although there were few gross or visceral anomaliies in either rats or rabbits, the incidence of osseous anomalies in rats was of both statistical and biologic significance. Rats given PGF2alpha (M) by subcutaneous injection beginning on the 15th day of gestation in a perinatal-postnatal study were most sensitive to the abortifacient. In that study the no-effect level was 0.0001 mg/kg. At larger doses ranging from 0.25 to 0.003 mg/kg, treatment was associated with abortion, poor viability, and impaired lactation.