A new model for embryotoxicity testing: teratogenicity and pharmacokinetics of valproic acid following constant-rate administration in the mouse using human therapeutic drug and metabolite concentrations

The limitations of a conventional testing procedure for embryotoxicity-multiple dosing throughout the organogenesis period of the mouse or rat-are discussed for drugs such as valproic acid (VPA) which exhibit pharmacokinetic properties in these species which are very different from those in the human. Administration of VPA to the mouse, once each day, resulted in peak plasma drug concentrations 10 fold higher than human therapeutic plasma levels, after which the drug levels rapidly decreased to insignificant levels which persisted until the time of the next dose. Dose-dependent growth retardation, a sharp increase in the resorption rate and a high incidence of exencephaly were observed with this dosing regimen. A new mouse model was developed where constant-rate application of the drug with osmotic minipumps resulted in drug levels throughout the organogenesis period which were similar to those observed during human therapy. Such therapeutic drug levels produced a slight but significant fetal growth retardation and increased resorption rates, but not exencephaly. It is suggested that maintaining plasma concentrations in the experimental animal comparable to human therapeutic drug levels should offer a more realistic model for drug-embryotoxicity testing.