Preliminary study of the effects of carbamazepine on congenital orofacial defects in offspring of A/J mice.
Carbamazepine (CBZ; Tegretol) is an effective anticonvulsant drug. We assessed putative CBZ teratogenicity in a sensitive animal model, the A/J mouse. Plasma CBZ levels were determined by gas-liquid chromatography. To achieve the accepted human plasma therapeutic range (TR) of CBZ (8-12 micrograms/ml), up to a 6X human oral dose was given. Test Group A received 300 mg pure crystalline CBZ/kg, suspended in 1.25% carboxymethylcellulose (CMC), at 6 a.m., noon, 6 p.m., and midnight on gestational day 10 (previously determined to be the peak sensitive time for cleft lip and palate induction in the A/J) and at 6 a.m. on day 11. Test Group B received 150 mg/kg of an experimental CBZ elixir (Tegretal Sirup) on the same regimen. Plasma levels rose to above TR within 15 min, then fell steadily, exiting the TR by 5 hr postgavage. Test Group C was given the experimental CBZ elixir at 4-h intervals for 36 hr. The rapid rise and fall of CBZ plasma levels again occurred, but the time within the therapeutic range was greatly increased (through 6 p.m. day 11). Control groups received the appropriate quantity of the CMC vehicle. Fetuses were harvested on day 17. Compared to control animals, none of the CBZ regimens was associated with a major increase in incidence of cleft lip or palate.
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D002220:Carbamazepine / Q000097:blood / Q000378:metabolism / Q000633:toxicity*; D002971:Cleft Lip / Q000139:chemically induced*; D002972:Cleft Palate / Q000139:chemically induced*; D005260:Female; D008431:Maternal-Fetal Exchange; D051379:Mice; D008815:Mice, Inbred Strains; D011247:Pregnancy
D002220:Carbamazepine