Prenatal diazepam: distribution and metabolism in perinatal rats.
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 muCi/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.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D001711:Biotransformation; D001812:Blood-Brain Barrier; D001921:Brain / Q000187:drug effects; D003975:Diazepam / Q000378:metabolism* / Q000633:toxicity; D005260:Female; D007774:Lactation; D008431:Maternal-Fetal Exchange; D008657:Metabolic Clearance Rate; D009115:Muridae; D011247:Pregnancy; D014018:Tissue Distribution
D003975:Diazepam