Abstract
Evaluation of Valproic Acid (VPA) Developmental Toxicity and Pharmacokinetics in Sprague-Dawley Rats.BINKERD, P. E., ROWLAND, J. M., NAU, H., and HENDRICKX, A. G. (1988). Fundam Appl. Toxicol. 11, 485-493. This study was undertaken to assess the pharma cokinetics and developmental toxicity of the anticonvulsant, valproic acid (VPA), a human teratogen, in Sprague-Dawley rats. Oral administration of 200-800 mg/kg VPA (5-20X human 3 therapeutic dose) from Gestational Days (GD) 8 to 17 resulted in increasing maternal toxicity at the higher doses with 100% maternal lethality at 800 mg/kg. Although there was an increased incidence of resorptions at 600 mg/kg (48 ± 43%) compared to controls (18 ± 24%), it was not statistically significant. Fetal examination on GD 20 revealed dose-dependent fetal growth retardation (p ≤ 0.05) as evidenced by decreased fetal weight and length in addition to underossi-fication of both the axial and appendicular skeleton. The incidence of skeletal defects, including abnormal vertebrae, ribs, and craniofacial dysmorphia, also increased with higher doses of VPA. Cardiac anomalies observed in the two highest treatment groups consisted of great vessel malformations with or without associated ventricular septal defects (VSDs). Urogenital defects were 3 also noted in the 600 mg/kg group. The plasma elimination half-life on GD 8 was 1.0 ± 0.3 hr at 200 mg/kg and 2.3 ± 0.7 hr at 600 mg/kg. Maximal concentrations of total and free drug were 341 ± 18 μg/ml and 181 ± 11 μg/ml, respectively, in the low-dose group and 911 ± 379 μg/ml and 542 ± 224 μ%/ml in the high-dose group. No significant changes in any pharmacokinetic 3 parameters (t1/2, AUC, Cmax, tmax) were observed over the 10-day treatment period at either dose level.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 485-593 |
| Number of pages | 109 |
| Journal | Toxicological Sciences |
| Volume | 11 |
| Issue number | 1 |
| DOIs | |
| State | Published - 1988 |
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Evaluation of valproic acid (vpa) developmental toxicity and pharmacokinetics in sprague-dawley rats. / Binkerd, P. E.; Rowland, J. M.; Nau, H.; Hendrickx, Andrew G.
In: Toxicological Sciences, Vol. 11, No. 1, 1988, p. 485-593.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Evaluation of valproic acid (vpa) developmental toxicity and pharmacokinetics in sprague-dawley rats
AU - Binkerd, P. E.
AU - Rowland, J. M.
AU - Nau, H.
AU - Hendrickx, Andrew G
PY - 1988
Y1 - 1988
N2 - Evaluation of Valproic Acid (VPA) Developmental Toxicity and Pharmacokinetics in Sprague-Dawley Rats.BINKERD, P. E., ROWLAND, J. M., NAU, H., and HENDRICKX, A. G. (1988). Fundam Appl. Toxicol. 11, 485-493. This study was undertaken to assess the pharma cokinetics and developmental toxicity of the anticonvulsant, valproic acid (VPA), a human teratogen, in Sprague-Dawley rats. Oral administration of 200-800 mg/kg VPA (5-20X human 3 therapeutic dose) from Gestational Days (GD) 8 to 17 resulted in increasing maternal toxicity at the higher doses with 100% maternal lethality at 800 mg/kg. Although there was an increased incidence of resorptions at 600 mg/kg (48 ± 43%) compared to controls (18 ± 24%), it was not statistically significant. Fetal examination on GD 20 revealed dose-dependent fetal growth retardation (p ≤ 0.05) as evidenced by decreased fetal weight and length in addition to underossi-fication of both the axial and appendicular skeleton. The incidence of skeletal defects, including abnormal vertebrae, ribs, and craniofacial dysmorphia, also increased with higher doses of VPA. Cardiac anomalies observed in the two highest treatment groups consisted of great vessel malformations with or without associated ventricular septal defects (VSDs). Urogenital defects were 3 also noted in the 600 mg/kg group. The plasma elimination half-life on GD 8 was 1.0 ± 0.3 hr at 200 mg/kg and 2.3 ± 0.7 hr at 600 mg/kg. Maximal concentrations of total and free drug were 341 ± 18 μg/ml and 181 ± 11 μg/ml, respectively, in the low-dose group and 911 ± 379 μg/ml and 542 ± 224 μ%/ml in the high-dose group. No significant changes in any pharmacokinetic 3 parameters (t1/2, AUC, Cmax, tmax) were observed over the 10-day treatment period at either dose level.
AB - Evaluation of Valproic Acid (VPA) Developmental Toxicity and Pharmacokinetics in Sprague-Dawley Rats.BINKERD, P. E., ROWLAND, J. M., NAU, H., and HENDRICKX, A. G. (1988). Fundam Appl. Toxicol. 11, 485-493. This study was undertaken to assess the pharma cokinetics and developmental toxicity of the anticonvulsant, valproic acid (VPA), a human teratogen, in Sprague-Dawley rats. Oral administration of 200-800 mg/kg VPA (5-20X human 3 therapeutic dose) from Gestational Days (GD) 8 to 17 resulted in increasing maternal toxicity at the higher doses with 100% maternal lethality at 800 mg/kg. Although there was an increased incidence of resorptions at 600 mg/kg (48 ± 43%) compared to controls (18 ± 24%), it was not statistically significant. Fetal examination on GD 20 revealed dose-dependent fetal growth retardation (p ≤ 0.05) as evidenced by decreased fetal weight and length in addition to underossi-fication of both the axial and appendicular skeleton. The incidence of skeletal defects, including abnormal vertebrae, ribs, and craniofacial dysmorphia, also increased with higher doses of VPA. Cardiac anomalies observed in the two highest treatment groups consisted of great vessel malformations with or without associated ventricular septal defects (VSDs). Urogenital defects were 3 also noted in the 600 mg/kg group. The plasma elimination half-life on GD 8 was 1.0 ± 0.3 hr at 200 mg/kg and 2.3 ± 0.7 hr at 600 mg/kg. Maximal concentrations of total and free drug were 341 ± 18 μg/ml and 181 ± 11 μg/ml, respectively, in the low-dose group and 911 ± 379 μg/ml and 542 ± 224 μ%/ml in the high-dose group. No significant changes in any pharmacokinetic 3 parameters (t1/2, AUC, Cmax, tmax) were observed over the 10-day treatment period at either dose level.
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U2 - 10.1093/toxsci/11.1.485
DO - 10.1093/toxsci/11.1.485
M3 - Article
VL - 11
SP - 485
EP - 593
JO - Toxicological Sciences
JF - Toxicological Sciences
SN - 1096-6080
IS - 1
ER -