Variability in the developmental toxicity of bropirimine with the day of administration.
The aim of this study was to determine the mechanism by which bropirimine exerts its developmental toxicity. This drug is an immunomodulator and interferon inducer with antiviral and antitumor activities in experimental models. Timed-pregnant Upj:TUC(SD)spf (Sprague-Dawley) rats were given a single oral (gastric intubation) dose of bropirimine at 200 or 400 mg/kg (doses as high as 100 mg/kg/day have been employed in human cancer trials) on days 5, 6, 7, 8, 9, 10, 11, or 12 of gestation and in a second experiment on day 12, 13, 14, 15, 16, 17, 18, or 19 of gestation. The dams were killed 24 hours after dosing and their uterine contents examined. In a third experiment, bropirimine (400 mg/kg) was administered on day 4 of gestation and the uteri of different groups were examined on day 8, 9, 10, 11, or 12 of gestation. Serum progesterone levels were measured at sacrifice. In the first two experiments a battery of hematologic/clinical chemistry assays also were performed. In all three experiments, bropirimine-related maternal toxicity was observed; such toxicity was characterized by significant decreases in weight gain, relative to the concurrent vehicle controls, as well as significant differences in several blood parameters including platelets, white blood cells, alanine aminotransferase, and aspartate transaminase. In the first experiment, bropirimine treatment on day 11, but not day 12, resulted in significant decreases in the mean number of live embryos per litter. In the second experiment, significant decreases in the number of live fetuses per litter occurred 24 hours after dosing on day 18 (200 and 400 mg/kg groups) or day 19 (400 mg/kg group). Decreases in serum progesterone appeared to correlate well with the embryolethal effects seen after treatment between days 6 and 11 of gestation, but not with the fetal lethality seen when treatment was given on day 17 or 18. The decreases in serum progesterone levels found most likely were the result of a luteolytic effect, although it is unknown if bropirimine has a direct or indirect effect on the corpora lutea. In the third experiment, bropirimine treatment on day 4 of gestation resulted in only slight preimplantational losses, but significant decreases were found in mean number of live embryos per litter after day 9. Uterine decidual necrosis has been observed in the first experiment where bropirimine was given on day 11; however, treatment on day 4 resulted in an apparent decrease in decidual development but not necrosis.
Marks
T A
TA
Upjohn Company, Kalamazoo, Michigan 49001.
Black
D L
DL
Terry
R D
RD
Branstetter
D G
DG
Kirton
K T
KT
D000818:Animals; D003596:Cytosine / Q000031:analogs & derivatives* / Q000633:toxicity; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D005865:Gestational Age; D008431:Maternal-Fetal Exchange; D009336:Necrosis; D011247:Pregnancy; D011374:Progesterone / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains; D013723:Teratogens; D014591:Uterine Diseases / Q000139:chemically induced / Q000473:pathology*
D013723:Teratogens; D011374:Progesterone; D003596:Cytosine; C033560:bropirimine