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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 X 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.
A G Hendrickx, and
H Nau, and
P Binkerd, and
J M Rowland, and
J R Rowland, and
M J Cukierski, and
M A Cukierski
January 1990,
Reproductive toxicology (Elmsford, N.Y.),
A G Hendrickx, and
H Nau, and
P Binkerd, and
J M Rowland, and
J R Rowland, and
M J Cukierski, and
M A Cukierski
February 1981,
Epilepsia,
A G Hendrickx, and
H Nau, and
P Binkerd, and
J M Rowland, and
J R Rowland, and
M J Cukierski, and
M A Cukierski
January 1980,
Pediatric pharmacology (New York, N.Y.),
A G Hendrickx, and
H Nau, and
P Binkerd, and
J M Rowland, and
J R Rowland, and
M J Cukierski, and
M A Cukierski
June 1984,
Epilepsia,
A G Hendrickx, and
H Nau, and
P Binkerd, and
J M Rowland, and
J R Rowland, and
M J Cukierski, and
M A Cukierski
January 1991,
Life sciences,
A G Hendrickx, and
H Nau, and
P Binkerd, and
J M Rowland, and
J R Rowland, and
M J Cukierski, and
M A Cukierski
January 1986,
Drug metabolism and disposition: the biological fate of chemicals,
A G Hendrickx, and
H Nau, and
P Binkerd, and
J M Rowland, and
J R Rowland, and
M J Cukierski, and
M A Cukierski
August 1975,
Gastroenterology,
A G Hendrickx, and
H Nau, and
P Binkerd, and
J M Rowland, and
J R Rowland, and
M J Cukierski, and
M A Cukierski
April 1987,
Teratology,
A G Hendrickx, and
H Nau, and
P Binkerd, and
J M Rowland, and
J R Rowland, and
M J Cukierski, and
M A Cukierski
January 1979,
Proceedings of the Western Pharmacology Society,
A G Hendrickx, and
H Nau, and
P Binkerd, and
J M Rowland, and
J R Rowland, and
M J Cukierski, and
M A Cukierski
October 1984,
Epilepsia,
