Teratogenicity of etretinate during early pregnancy in the rat and its correlation with maternal plasma concentrations of the drug.
Sprague-Dawley female rats were treated with a single oral dose of 0 (vehicle), 10, or 25 mg/kg of etretinate (ET), an aromatic retinoid, on gestation day 6, 7, or 8. While treatment on day 8 with both dosages of ET was highly teratogenic, no evidence of embryotoxicity, considered to be treatment related, was observed when the same doses were administered on day 6 or 7. We concluded that the rat embryo is not susceptible to teratogenic effects of ET on gestation day 6 or 7 and that day 8 is the earliest susceptible period for ET teratogenesis. This may well be true of retinoids as a class since we have observed similar results for all-trans- and 13-cis-retinoic acids (unpublished findings). In another study, mated rats were treated with a single oral dose of ET on day 8. No evidence of embryotoxicity was observed at dosages of 1, 3, and 6 mg/kg; in contrast, treatment with 10, 15, or 25 mg/kg of ET resulted in an increasingly greater number of malformed fetuses and resorptions. Plasma concentrations of ET and three metabolites [acitretin (AC), 13-cis-etretinate (13-cis-ET), and 13-cis-acitretin (13-cis-AC)) were determined in mated rats given a single oral non-teratogenic (3 or 6 mg/kg) or teratogenic (10 or 25 mg/kg) dose of ET on gestation day 8. The AUC0----24hr values of ET and AC, the major metabolite and suspected proximal teratogen, were roughly proportional to the administered dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Agnish
N D
ND
Department of Toxicology and Pathology, Hoffmann-La Roche, Inc., Nutley, New Jersey 07110.
Vane
F M
FM
Rusin
G
G
DiNardo
B
B
Dashman
T
T
D017255:Acitretin; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005050:Etretinate / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D005333:Fetus / Q000187:drug effects; D008297:Male; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D013723:Teratogens; D014212:Tretinoin / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism
D013723:Teratogens; D014212:Tretinoin; D005050:Etretinate; D017255:Acitretin