Lack of teratogenicity of trans-2-ene-valproic acid compared to valproic acid in rats.
The teratogenicity of trans-2-ene-valproic acid (300 and 400 mg/kg) was compared with that of valproic acid (VPA; 300 mg/kg) and controls (corn oil) administered by gavage to Sprague-Dawley CD rats on embryonic (E) days 7-18. At the 300 mg/kg dose, trans-2-ene-VPA produced no change in maternal weight, number of implantations, proportion of resorptions, proportion of malformations, or fetal weight. By contrast, the same dose of VPA (300 mg/kg) reduced maternal weight during gestation, increased malformations (12.0% vs. 0.7% in controls), and reduced fetal body weight by 25.1%. An even higher dose of trans-2-ene-VPA (400 mg/kg) produced a reduction in maternal body weight during treatment and reduced fetal body weight (by 7.9%), but did not increase resorptions or malformations in the fetuses. On day E18, maternal serum drug concentrations of VPA were higher in the VPA-treated group compared with those of trans-2-ene-VPA in the trans-2-ene-VPA-treated groups at 1 hr posttreatment. At 6 hr posttreatment the reverse was seen. trans-2-ene-VPA may be absorbed more rapidly and distributed differently than VPA. Overall, the data support the view that trans-2-ene-VPA at equal or higher doses than VPA is not teratogenic in rats.
Vorhees
C V
CV
Institute for Developmental Research, Children's Hospital Research Foundation, Cincinnati, Ohio 54229-2899.
Acuff-Smith
K D
KD
Weisenburger
W P
WP
Minck
D R
DR
Berry
J S
JS
Setchell
K D
KD
Nau
H
H
D000818:Animals; D001835:Body Weight; D004622:Embryo, Mammalian / Q000187:drug effects; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D013723:Teratogens; D014635:Valproic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000633:toxicity*
D005229:Fatty Acids, Monounsaturated; D013723:Teratogens; C014168:2-propyl-2-pentenoic acid; D014635:Valproic Acid