Comparative developmental toxicity and metabolism of nitrazepam in rats and mice.
This study was designed to evaluate the developmental toxicity of nitrazepam (NZ) in Sprague-Dawley rats and ICR mice and to determine the metabolic factors which modulate susceptibility to the developmental effects of NZ. Rats were treated orally with a single dose of NZ at 300 mg/kg on Day 12 of gestation. Mice received one dose of 300 mg/kg NZ via gavage between Days 9 and 14 of gestation. NZ administration resulted in a significant incidence of malformations in rats, while no evidence of teratogenic action was observed in mice. Pronounced species differences in the metabolism of NZ were observed. In rats, 7-acetylaminonitrazepam (AANZ) was detected as the major metabolite in plasma and embryos, whereas in mice, only small amounts of this product were found. The rate of N-acetylation of 7-aminonitrazepam (ANZ) to AANZ was 8.5-fold greater in rat liver cytosol than that in mouse liver cytosol. In contrast, the rate of deacetylation of AANZ to ANZ was 9-fold greater in mouse liver microsomes than that in rat liver microsomes. The developmental effects of authentic metabolites of NZ were studied in the two species. A single oral administration of 300 mg/kg ANZ to pregnant animals produced a significant incidence of malformations in rats, but not in mice. On the other hand, AANZ was teratogenic in both species. These results suggest that the difference in the susceptibility to NZ-induced teratogenicity between rats and mice may be related to differences in the levels of N-acetyltransferase and deacetylase, and that AANZ may be involved in the teratogenic mechanism.
Takeno
S
S
Department of Pharmacology, School of Pharmacy, Hokuriku University, Kanazawa, Japan.
Hirano
Y
Y
Kitamura
A
A
Sakai
T
T
D000014:Abnormalities, Drug-Induced; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D008099:Liver / Q000378:metabolism; D008431:Maternal-Fetal Exchange; D051379:Mice; D008813:Mice, Inbred ICR; D009567:Nitrazepam / Q000031:analogs & derivatives / Q000378:metabolism* / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
C043577:7-aminonitrazepam; C043576:7-acetamidonitrazepam; D009567:Nitrazepam