© 1989 Oxford University Press
research-article |
Bropirimine-Induced Embryolethality after Oral Administration to the Pregnant Rat
*Reproductive and Developmental Toxicology, The Upjohn Company Kalamazoo, Michigan 49001
Cancer and Infectious Diseases Research, The Upjohn Company Kalamazoo, Michigan 49001
Received July 5, 1988; accepted December 13, 1988
Oral bropirimine (an immunomodulator shown to induce interferon) was administered to timed-pregnant Sprague-Dawley rats in five experiments utilizing several different dosing schedules. Concentrations of 100, 200, and 400 mg/kg of bropirimine were used. Interferon levels were determined in maternal serum, spleen, and whole embryo extracts and uterine contents were evaluated for survival of the embryos. Maternal toxicity occurred in all experiments as evidenced by dose-related decreases in body weight during the first 24 hr postdosing. Hematoxicology analyses of maternal serum revealed significant decreases in urea nitrogen, potassium, and albumin, along with increases in aspartate transaminase, alanine transaminase, and total bilirubin, in bropirimine-treated dams as compared to the vehicle controls. In addition, the means for maternal thymus weight decreased while the means for spleen weight increased with increasing concentration of bropirimine. As compared to the vehicle controls, interferon titers were high in maternal serum, maternal spleen, and, to a lesser extent, whole embryos, 2 hr postdosing, but had decreased or were below detectable levels 24 hr postdosing. Embryolethality was pronounced (increases in pre- and postimplantational loss) after a single dose (Gestation Day 3, 4, 5, 8, 9, or 10) of bropirimine, as well as after 7 or 8 consecutive days (Gestation Days 6–12 or 6–13) of treatment. Although embryotoxicity never occurred in these experiments in the absence of pronounced maternal toxicity, the pregnant dams never died as the result of bropirimine treatment, whereas the embryos frequently failed to survive.