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.

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Preimplantation stages were collected from normal rhesus monkeys by flushing of the uterine lumen. There was a high incidence of abnormal morulae and blastocysts (25%), as well as abnormal cells and cell death in otherwise normal blastocysts. In addition to cell and nuclear fragmentation, clustering of organelles in the center of the blastomeres was a common feature in early degeneration of ova and blastomeres. Large isolated cells that lagged in cytological development were found both in large numbers in an abnormal blastocyst and as individual cells in normal blastocysts. One apparently abnormal blastocyst was composed of normal trophoblast and inner cell mass cells, but lacked desmosomes and was collapsed. The cytological study of development of the blastocyst indicated that assessment of viability of primate blastocysts by light microscopic observation of morulae and blastocyst stages is probably more fraught with difficulty than might appear from studies of common laboratory animals.