Valproic acid developmental toxicity and pharmacokinetics in the rhesus monkey: An interspecies comparison

Andrew G Hendrickx, H. Nau, P. Binkerd, J. M. Rowland, J. R. Rowland, M. J. Cukierski, M. A. Cukierski

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Abstract

This study was undertaken to assess the developmental toxicity and drug distributional and metabolic characteristics of prenatal valproic acid (VPA) exposure in rhesus monkeys. Oral administration of 20–600 mg/kg/ day VPA (approximately 1–15 × human therapeutic dose) to 33 animals on variable gestational days (GD) during organogenesis resulted in dose‐dependent developmental toxicity manifested as increased embryo/fetal mortality, intrauterine growth retardation, and craniofacial and skeletal defects. Biphasic plasma elimination curves were observed for total and free VPA on the first (GD 21) and last (GD 50) days of treatment in the 100‐ and 200‐mg/kg/day dose groups. VPA exhibited dose‐independent elimination kinetics at the plasma concentrations observed in this study. There was no significant change in pharmacokinetic parameters (maternal plasma elimination rate, area under the curve, peak plasma concentration) between the first and last days of treatment at either dose level. Placental transfer studies indicated that embryos were exposed to half the free VPA concentrations present in maternal plasma on GD 37. Comparisons of interspecies sensitivity to VPA‐induced developmental toxicity in the mouse, rat, monkey, and man are made.

Original languageEnglish (US)
Pages (from-to)329-345
Number of pages17
JournalTeratology
Volume38
Issue number4
DOIs
StatePublished - 1988

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Pharmacokinetics
Valproic Acid
Macaca mulatta
Toxicity
Plasmas
Embryonic Structures
Mothers
Fetal Mortality
Organogenesis
Fetal Growth Retardation
Drug-Related Side Effects and Adverse Reactions
Area Under Curve
Haplorhini
Oral Administration
Rats
Animals
Therapeutics
Defects
Kinetics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Embryology
  • Toxicology
  • Developmental Biology
  • Health, Toxicology and Mutagenesis

Cite this

Hendrickx, A. G., Nau, H., Binkerd, P., Rowland, J. M., Rowland, J. R., Cukierski, M. J., & Cukierski, M. A. (1988). Valproic acid developmental toxicity and pharmacokinetics in the rhesus monkey: An interspecies comparison. Teratology, 38(4), 329-345. https://doi.org/10.1002/tera.1420380405

Valproic acid developmental toxicity and pharmacokinetics in the rhesus monkey : An interspecies comparison. / Hendrickx, Andrew G; Nau, H.; Binkerd, P.; Rowland, J. M.; Rowland, J. R.; Cukierski, M. J.; Cukierski, M. A.

In: Teratology, Vol. 38, No. 4, 1988, p. 329-345.

Research output: Contribution to journalArticle

Hendrickx, AG, Nau, H, Binkerd, P, Rowland, JM, Rowland, JR, Cukierski, MJ & Cukierski, MA 1988, 'Valproic acid developmental toxicity and pharmacokinetics in the rhesus monkey: An interspecies comparison', Teratology, vol. 38, no. 4, pp. 329-345. https://doi.org/10.1002/tera.1420380405
Hendrickx, Andrew G ; Nau, H. ; Binkerd, P. ; Rowland, J. M. ; Rowland, J. R. ; Cukierski, M. J. ; Cukierski, M. A. / Valproic acid developmental toxicity and pharmacokinetics in the rhesus monkey : An interspecies comparison. In: Teratology. 1988 ; Vol. 38, No. 4. pp. 329-345.
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