Gestational Age Dependency in the Prenatal Toxicity and in the Disposition Kinetics of the Novel Anticonvulsant HEPP (D,L-3-Hydroxy-3-ethyl-3-phenylpropionamide) after Subcutaneous Administration in Pregnant Rats

Abstract

HEPP (D,L-3-hydroxy-3-ethyl-3-phenylpropionamide) is a novel anticonvulsant with promising anticonvulsant profile, which is being actively researched. The potential maternal and embryo/fetal toxicities of HEPP were evaluated in pregnant rats following subcutaneous (s.c.) administration during organogenesis (gestation days 6 through 14, GDs 6–14) and the fetal period (GDs 14–21). Single- and multiple-dose pharmacokinetics were also evaluated at the same periods in order to establish possible correlations with some maternal or embryo/fetal toxicity end points. Embryotoxicity was mainly indicated by a significant dose-concentration dependency in the increase in resorptions, high percentage of fully resorbed litters, and decrease in embryo body weights during the GD6–14 dosing period. No gross external alterations were observed in live fetuses. There was no indication of maternal toxicity; but a marked increase in maternal body weight was evident following dosing from GD14 to GD21. The maternal plasma profile following single subcutaneous dose of 50 mg/kg on both GD14 and GD21 showed a monoexponential elimination pattern. Statistically significant differences between treatments (GD14 versus GD21) were observed in elimination ( kel = 0.12 versus 0.15 h−1), absorption ( ka = 2.01 versus 3.14 h−1), maximum plasma concentration time points ( Tmax = 1.49 versus 1.01 h); maximum plasma concentration ( Cmax = 40.23 versus 36.31 μg/ml) and areas under the concentration-time curve (AUCs0– ∞ = 421.88 versus 274 μg h/ml. Based on comparisons of Cmax, Tmax, and AUCs0– ∞ between the actual data and single intraperitoneal (i.p.) data previously published, the s.c. administration exhibited slower disposition and higher absorbed amount. After multiple-dose administrations of 50 and 100 mg/kg every 12 h (07:00 and 19:00 h), steady-state plasma levels were lower than the computer prediction, and only slight accumulation was observed. In both dosing periods HEPP levels were similar in mothers and offspring at steady-state conditions. The high incidence of embryo death and reduced embryo weight at GD6–14 dosing compared to GD14–21 dosing suggest that embryos are more sensitive to the deleterious effects of HEPP than fetuses; however, the faster elimination observed at late gestation could also contribute to the lower toxicity observed during the fetal period. Because the maternal HEPP plasma levels and the AUC values were positively correlated with embryo/fetal toxicity end points, both pharmacokinetic parameters could be reliable indicators of offspring exposure and consequently of potential toxicity. These data suggest that the length of time that HEPP is present in the maternal plasma at a sufficiently high concentration could be determinant of adverse effects in the offspring.