Pharmacokinetics of d, l-3-hydroxy-3-ethyl-3-phenylpropionamide (HEPP) in pregnant rats at different stages of gestation and maternal–fetal disposition during late pregnancy

Abstract

The pharmacokinetics of d, l-3-hydroxy-3-ethyl-3-phenylpropionamide (HEPP), an investigational anticonvulsant drug, was evaluated in nonpregnant and in pregnant rats on gestation day (GD) 7, 12, and 21 after an intraperitoneal (i.p.) dose of 50 mg/kg. Maternal–fetal disposition in the GD21 group was also evaluated. In all groups, HEPP was rapidly absorbed and the disposition was well described by an open two-compartment kinetic model. The most pronounced effects of pregnancy on the kinetics of HEPP were observed at GD21 in which significant increases in the first-order hybrid disposition rate constants α and β, with corresponding decreases in half-lives were observed. Gestation also affected the intercompartmental transfer rate constants k 12 and k 21, specially at GD12 and at GD21. These changes could be associated with the physiologic increases in blood flow and cardiac output of pregnancy. There was also a slight decrease in the apparent volume of distribution at GD21, and a progressive decrease in the clearance values normalized by the body weight. No other significant differences in kinetic parameters were observed. On GD21, HEPP rapidly transfers from maternal blood to fetuses, to reach concentrations in the placenta and fetuses slightly higher than those of the maternal plasma (fetal:maternal ratio ranging from 1.07 to 1.45). After equilibrium, the concentrations in maternal, placental, and fetal tissues decreased in parallel.