Diazepam (DZ) placental transfer in pregnant women at term, following single or repeated drug administration by various routes, was evaluated. DZ and its metabolite N-demethyldiazepam (NDZ) were constantly present in umbilical cord plasma at concentrations comparable to the mother's shortly after drug administration. N-methyloxazepam (MOX) was detected in cord plasma only in a limited number of cases following chronic DZ treatment. Postmortem analysis of fetal tissue concentrations showed accumulation of NDZ in heart and lungs. Differences in NDZ concentrations between venous cord (VC) and arterial cord (AC) plasms suggest metabolic degradation of DZ in the fetus. The DZ apparent plasma half-life in the newborn was found to be longer (31 plus or minus 2 hr) than previously observed in infants and children. The low drug clearance appears to be linked to reduced urinary excretion of hydroxylated metabolites, suggesting limited capability to dispose of DZ in the newborn.
[Show abstract][Hide abstract] ABSTRACT: Presently, no well-validated predictive tools are available for human placental transfer. We studied the transplacental passage of diazepam (DZP) in a recirculating dual human placental perfusion and compared the data with in vivo clinical data from the literature.
Term placentas from healthy mothers without medication were used. The dual, recirculating perfusion technique was used. DZP (2 microg/ml, n = 4; 200 ng/ml, n = 3) and the reference compound antipyrine (100 microg/ml) were added into the maternal circulation simultaneously. The disappearance of drugs from the maternal circulation and appearance into the fetal circulation were followed every 15 min for 2 h.
DZP was detectable in the fetal circulation within 15 min in all of the perfusions indicating rapid transfer. DZP concentrations in the maternal circulation were higher than in the fetal circulation throughout the perfusion with both initial concentrations. At the end of the perfusion, the feto-maternal ratio was 0.48 +/- 0.11 (mean +/- S.D.) and the transfer from the maternal to the fetal compartment 18.4 +/- 3.6% with 2 microg/ml of DZP and 0.55 +/- 0.10 and 20.5 +/- 3.1% with 200 ng/ml of DZP, respectively. DZP concentrations in the perfused area of the placenta were in average 2 times higher than in the maternal perfusate and 3.6 times higher than in the fetal perfusate. Total recovery of DZP from samples, perfusion fluid, and perfused tissue was 37.6 +/- 21%.
Since animal studies in vivo do not accurately predict human placental transfer and it is problematic to study placental transfer of drugs in humans in vivo, the present human placental perfusion system could serve as one part of a test battery for fetotoxicity. However, although our earlier studies and those from the literature indicate a good correlation between in vivo and placental perfusion data, the present study shows this is not the case for all drugs.
Journal of Pharmacological and Toxicological Methods 11/2002; 48(3):131-8. DOI:10.1016/S1056-8719(03)00038-8 · 2.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: During pregnancy and lactation, women often receive medications that have CNS activity. However, the developmental consequences for infants of perinatal exposure to these medications have not been fully characterised. Some CNS drugs are associated with congenital anomalies and delayed development. An obvious dilemma arises for clinicians, since maternal benefits of pharmacotherapy must be judiciously weighed against risk to the infant. Treatment plans should be directed to the individual needs of the mother and child, in addition to enhancing safety for the dyad.
Preclinical studies have demonstrated long term effects of CNS drugs on neuro-development, yet findings are limited on similar risks in humans. In general, clinical information has been gleaned from case reports and uncontrolled studies. Therefore, healthcare providers are burdened with the responsibility of making clinical decisions with minimal data.
One solution for enhancing decision-making is to appreciate underlying principles applicable to the evaluation of neurodevelopmental protocols. If the objective is to evaluate developmental effects of CNS drugs, paradigms should address basic tenets of neurodevelopment and drug disposition. Factors related to the general condition of the mother are often neglected. Frequently the data on dose, duration and period of drug exposure are incomplete. Since systematic follow-up assessments generally are not performed, subtle effects on mental acuity and behaviour may have been missed. These methodological deficiencies suggest that further investigation is warranted.
Nonetheless, some data on the potential for persistent effects are available. Antidepressants taken during pregnancy and lactation do not appear to be teratogenic or associated with acute adverse effects, but data on development are inadequate. On the other hand, delayed motor development was reported following administration of benzodiazepines during gestation. Adverse effects have not been found from lactational exposure to benzodiazepines, but caution is advised because of potential accumulation in infants. Effects on development and learning were linked to in utero exposure to anticonvulsants. Finally, delays in development were reported in children exposed to antipsychotics in breast milk. Because of teratogenic risks associated with CNS medications, exposed infants should be carefully monitored.
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