Teratogenic activity and metabolism of primidone in the mouse.

Primidone, 25, 50, 100, and 150 mg/kg, was administered orally to mice of the I.C.I. strain from days 6-16 of pregnancy. The fetuses were removed by caesarian section on day 19 and examined by dissection and alizarin staining for gross structural and skeletal defects. The most common abnormalities found were palatal defects with full-length or submucosal clefts. In the controls--25, 50, 100, and 150 mg/kg groups--the incidence of palatal defects was 0/85, 16/84, 18/117, 19/102, and 17/92 fetuses, respectively. Essentially no other major or minor drug-related abnormalities were found. The metabolism of primidone in the pregnant and nonpregnant mouse was also studied and shown to be similar to that previously reported in the rat. Peak blood levels of primidone were obtained after 1 hr; they fell to very low levels by 6 hr. and were completely cleared by 24 hr. The metabolites produced, PEMA and phenobarbital, are similar to those produced in other species including man. Blood levels following single oral doses of 5 to 150 mg/kg were dose-related so that no explanation for the lack of dose-related teratogenic effect was found.