Abstract
The anticonvulsant, valproic acid (VPA) is a suspected human teratogen. This study, employing the rhesus monkey as an animal model, demonstrates that VPA has a significant teratogenic potential in the monkey. Timed pregnant monkeys were exposed orally to VPA at approx. 1X, 10X, and 30X (20, 200, and 600 mg/kg/day, respectively) the human therapeutic dose, daily, during organogenesis (gestation days 21-50). All fetuses of mothers exposed to greater than 1X exhibited some form of embryotoxicity. The highest dose, 30X, was 110% embryolethal, while offspring of the 10X dose group exhibited craniofacial and skeletal defects, and low body weights. Maternal pharmacokinetic parameters and plasma metabolites were determined for VPA on the first and last day of dosing for the 10X dose group. Comparison on the kinetic and metabolite data with that obtained for man indicates that the rhesus monkey is a good model for predicting the teratogenic potential of VPA in the human.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 111-119 |
| Number of pages | 9 |
| Journal | Toxicology |
| Volume | 39 |
| Issue number | 2 |
| DOIs | |
| State | Published - 1986 |
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Keywords
- 2-Propylpentanoic acid
- Pharmacokinetics
- Rhesus monkey
- Teratology
- Valporic acid
ASJC Scopus subject areas
- Toxicology
Cite this
Predicting the human teratogenic potential of the anticonvulsant, valproic acid, from a non-human primate model. / Mast, Terryl J.; Cukierski, Mark A.; Nau, Heinz; Hendrickx, Andrew G.
In: Toxicology, Vol. 39, No. 2, 1986, p. 111-119.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Predicting the human teratogenic potential of the anticonvulsant, valproic acid, from a non-human primate model
AU - Mast, Terryl J.
AU - Cukierski, Mark A.
AU - Nau, Heinz
AU - Hendrickx, Andrew G
PY - 1986
Y1 - 1986
N2 - The anticonvulsant, valproic acid (VPA) is a suspected human teratogen. This study, employing the rhesus monkey as an animal model, demonstrates that VPA has a significant teratogenic potential in the monkey. Timed pregnant monkeys were exposed orally to VPA at approx. 1X, 10X, and 30X (20, 200, and 600 mg/kg/day, respectively) the human therapeutic dose, daily, during organogenesis (gestation days 21-50). All fetuses of mothers exposed to greater than 1X exhibited some form of embryotoxicity. The highest dose, 30X, was 110% embryolethal, while offspring of the 10X dose group exhibited craniofacial and skeletal defects, and low body weights. Maternal pharmacokinetic parameters and plasma metabolites were determined for VPA on the first and last day of dosing for the 10X dose group. Comparison on the kinetic and metabolite data with that obtained for man indicates that the rhesus monkey is a good model for predicting the teratogenic potential of VPA in the human.
AB - The anticonvulsant, valproic acid (VPA) is a suspected human teratogen. This study, employing the rhesus monkey as an animal model, demonstrates that VPA has a significant teratogenic potential in the monkey. Timed pregnant monkeys were exposed orally to VPA at approx. 1X, 10X, and 30X (20, 200, and 600 mg/kg/day, respectively) the human therapeutic dose, daily, during organogenesis (gestation days 21-50). All fetuses of mothers exposed to greater than 1X exhibited some form of embryotoxicity. The highest dose, 30X, was 110% embryolethal, while offspring of the 10X dose group exhibited craniofacial and skeletal defects, and low body weights. Maternal pharmacokinetic parameters and plasma metabolites were determined for VPA on the first and last day of dosing for the 10X dose group. Comparison on the kinetic and metabolite data with that obtained for man indicates that the rhesus monkey is a good model for predicting the teratogenic potential of VPA in the human.
KW - 2-Propylpentanoic acid
KW - Pharmacokinetics
KW - Rhesus monkey
KW - Teratology
KW - Valporic acid
UR - http://www.scopus.com/inward/record.url?scp=0022646612&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0022646612&partnerID=8YFLogxK
U2 - 10.1016/0300-483X(86)90129-0
DO - 10.1016/0300-483X(86)90129-0
M3 - Article
C2 - 3085290
AN - SCOPUS:0022646612
VL - 39
SP - 111
EP - 119
JO - Toxicology
JF - Toxicology
SN - 0300-483X
IS - 2
ER -