Teratogenicity of carbamazepine in rats

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Abstract
The teratogenicity of carbamazepine (CBZ) was investigated in Sprague‐Dawley CD rats at doses of 0, 200, 400, and 600 mg/kg administered by gavage in corn oil on days 7–18 of gestation in a dosage volume of 2 ml/kg. The CBZ‐600 dose was maternally toxic in that dams in this group weighed 30.6% less than controls by E20. This group had significantly increased resorptions, reduced live fetal weight (51.6% less than controls), and increased skeletal and visceral abnormalities. The CBZ‐400 dose also significantly reduced maternal weight gain during gestation to 26.6% less than controls by E20. No significant increase in resorptions occurred in this group; live fetuses weighed 42.9% less than controls and showed an increase in visceral, but not skeletal, abnormalities. The CBZ‐200 dose did not significantly affect maternal weight gain or increase resorptions or fetal abnormalities but did reduce fetal body weight (20.3% less than controls). Maternal serum total CBZ concentrations 1 hr after the final dose were 22.9, 27.9, and 34.4 μg/ml for the 200, 400, and 600 mg/kg groups, respectively. These levels were little changed 6 h post‐treatment. CBZ was 65–70% serum protein bound across dose groups. Human therapeutic levels of CBZ are 4–12 μg/ml and the drug is typically 80% serum protein bound. This suggests that abnormalities in rats occur at concentrations well above the human therapeutic range. However, a no‐effect level was not found for fetal body weight. Further experiments will be required to determine how much lower doses will need to be in order to find a no‐effect level for fetal body weight. Nevertheless, the present data suggest that CBZ is not potent at inducing malformations in rats.