Diazepam Metabolism in the Guinea Pig Materno-Fetal Model: Effects of Cigarette Smoke

ABSTRACT

The transplacental acquisition, disposition and biotransforma-tion of diazepam (DZ) was investigated in the pregnant guinea pig at 65–67 days of gestation following the administration of single oral doses of 10 mg/kg body weight, the dams and fetuses being euthanized 60 min post-treatment. Tissues (blood plasma, liver, brain, perirenal fat and placenta) were removed for drug residue analysis. Nordiazepam (NDZ) was the only metabolite produced by guinea pigs in vivo. Residues of DZ and NDZ were found in fetal tissues, indicating that the placenta was not an effective barrier. The influence of cigarette smoke on in vitro DZ biotransformation was studied by exposing pregnant guinea pigs (55–57 days of gestation) to ambient air (control) or cigarette smoke thrice daily for 10 consecutive days. At term (day 671, the fetuses were delivered by caesarian section for the preparation of hepatic and placental microsomes to measure the metabolism of DZ. DZ was converted at a slow rate into NDZ by fetal hepatic and placental microsomes in vitro. Exposure to cigarette smoke had no effect on DZ metabolism by the dam liver or by the placenta but a 2–4-fold increase in NDZ formation was observed in fetal hepatic microsomes.