In vivo and in vitro studies on fetal toxicity of benzodiazepines in rats.

In this study, we investigated whether the intensity in the embryotoxicity of benzodiazepines was related to maternal and fetal blood levels and also to their high binding to the fetoplacental structures in rats. Maternal and fetal levels of nitrazepam (NTZ) and nimetazepam were higher than the diazepam level after oral administration of these drugs (100 mg/kg). In vitro, the affinity of the drugs for the fetus corresponded to the drug levels in the maternal serum and fetus. In the embryo culture, NTZ had no direct teratogenicity but had embryocidal activity. On the contrary, the in vivo maternal serum treated with NTZ possessed both activities. From the above facts, and since there was no change in the in vivo embryotoxicity as a result of phenobarbital, it was suggested that the embryocidal activity of NTZ may be due to changes of maternal function depended upon the maternal serum.