Prenatal diazepam: Distribution and metabolism in perinatal rats

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Abstract
Previous investigations have revealed that prenatal exposure to diazepam (DZ) alters brain development and behavior in the offspring of rats and mice. In order to understand how DZ may affect the developing nervous system it is necessary to examine its metabolic fate in the neonate. It is therefore the aim of this study to investigate the disposition, metabolism, and persistence of DZ in the neonate. Dams were injected s.c. with 2.5 mg/kg of 14C DZ (10 μCi/day) on days 13–20 of gestation and their litters were fostered at birth. Dams killed within 24 hours postpartum and neonates killed at postnatal days 0, 10, and 20 were analyzed for 14C activity. Brain levels (pmoles DZ and metabolites/100 mg tissue SE) were 3.4 ± 0.3 in the dam and in the neonates were 3.2 ± 0.3 (day 0), 3.4 ± 0.3 (day 10), and undetectable at day 20. Neonatal peripheral tissue 14C activity was undetectable by day 10. Brain regional analysis indicates 14C is highest in the colliculi at day 0, but not at day 10. Brain levels of DZ, oxazepam (OXA), N-desmethyldiazepam (NDZ), and the glucuronide (GLU) determined by high-performance liquid chromatography (HPLC), were GLU (49%), DZ (28%), and NDZ (24%) in the dam; GLU (52%), DZ (24%), and NDZ (25%) in the day 0 neonate; and GLU (32%), DZ (12%), NDZ (39%), and OXA (19%) at day 10. The distribution and metabolism of 14C DZ that persists in the neonate following prenatal exposure differs from that which occurs in the dam. The neonatal brain contains OXA and a higher concentration of 14C exists in the colliculi region of day 0 neonates when compared with maternal brain. Prenatal 14C DZ activity persists longer in the neonatal brain than in peripheral tissue but all tissue levels are undetectable at day 20. Therefore, DZ and its pharmacologically active metabolites persist longest in the neonatal brain and could therefore alter both prenatal and postnatal developmental processes. However, no drug is present in the neonate at 20 days of age and therefore could not directly affect behavior measured then or at later ages.