Reversal of bropirimine developmental toxicity with progesterone.
Bropirimine is an immunomodulator with experimental antiviral and antitumor activities. This pyrimidinone has been found to be embryolethal at doses (200 and 400 mg/kg) that produce only transient maternal toxicity, when administered to pregnant Upj:TUC(SD)spf rats on specific days of gestation. Serum analyses carried out in previous studies have shown marked decreases in progesterone levels in the 24 hr following bropirimine administration. In the present study, each of four groups of 5 bred rats and four groups of 10 bred rats was given bropirimine (gastric intubation) on Day 10 of gestation. Also, on Day 10 of gestation, progesterone (0.25, 0.50, or 1.00 mg/rat) was administered (im) twice (12-hr interval) a day to three of the groups of 5 dams each that had received bropirimine. In addition, three of the groups of 10 dams each received progesterone (0.25, 0.50, or 1.00 mg/rat) twice a day on Days 10-19 of gestation. Another group of 5 dams received progesterone only (0.50 mg/rat, b.i.d.) on Day 10 while a group of 10 dams received this same dose of progesterone on Days 10-19 of gestation. The groups containing 5 dams each were killed 24 hr postdosing while the groups containing 10 dams each were killed on Day 20 of gestation. The uteri were removed from the dams and examined. Administration of bropirimine alone resulted in the death of 100% of the embryos, at both the 24-hr and the Gestation Day 20 terminations. Exogenous administration of progesterone protected against bropirimine-mediated embryolethality; however, maternal effects were not alleviated. Thus, it appears likely that the embryolethality of bropirimine is the result of interruption of progesterone release from, or synthesis by, the corpora lutea, rather than direct toxicity toward the embryo, or lethal defects during organogenesis (terata).
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Safety Pharmacology, Upjohn Company, Kalamazoo, Michigan 49001.
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Branstetter
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Kirton
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D000276:Adjuvants, Immunologic / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D003596:Cytosine / Q000031:analogs & derivatives* / Q000633:toxicity; D004622:Embryo, Mammalian / Q000187:drug effects*; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced; D010053:Ovary / Q000187:drug effects; D011374:Progesterone / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D011374:Progesterone; D003596:Cytosine; C033560:bropirimine