Effect of pregnancy on the disposition of valproate in rats.
The disposition of sodium valproate in pregnant rats was studied comparing with nonpregnant (control) rats. In the pregnant rats, the total plasma clearance decreased significantly (p less than 0.05) from 7.06 ml/min/kg of the control to 5.34 ml/min/kg, whereas the plasma elimination half-life of valproate did not change. The serum unbound fraction (fs) of pregnant rats increased remarkably. The fs of the fetal plasma was lower than that of the maternal serum in spite of the lower albumin (main binding protein for valproate) concentration in the fetal plasma. A non-linear serum (plasma) protein binding was observed both in the control and the fetal rats, but not observed in the pregnant rats. In the pregnant rats, the tissue-to-plasma concentration ratio (Kp) of the brain was higher than that in the control rats, whereas the Kp values of the liver and and lung were lower than those in the control rats. In other tissues, the Kp values did not show a significant difference. Rapid placental transfer was observed and the Kp value of the fetus was 0.43.
Kobayashi
S
S
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Takai
K
K
Iga
T
T
Hanano
M
M
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D005260:Female; D008297:Male; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution; D014635:Valproic Acid / Q000097:blood / Q000493:pharmacokinetics*
D001798:Blood Proteins; D014635:Valproic Acid