Pharmacokinetic and Biochemical Profiling of Sodium Dichloroacetate in Pregnant Ewes and Fetuses

Sodium dichloroacetate (DCA) is an investigational drug that shows promise in the treatment of acquired and congenital mitochondrial diseases, including myocardial ischemia and failure. DCA increases glucose utilization and decreases lactate production, so it may also have clinical utility in reducing lactic acidosis during labor. In the current study, we tested the ability of DCA to cross the placenta and be measured in fetal blood after intravenous administration to pregnant ewes during late gestation and labor. Sustained administration of DCA to the mother over 72 hours achieved pharmacologically active levels of DCA in the fetus and decreased fetal plasma lactate concentrations. Multicompartmental pharmacokinetics modeling indicated that drug metabolism in the fetal and maternal compartments is best described by the DCA inhibiting lactate production in both compartments, consistent with our finding that the hepatic expression of the DCA-metabolizing enzyme glutathione transferase zeta1 was decreased in the ewes and their fetuses exposed to the drug. We provide the first evidence that DCA can cross the placental compartment to enter the fetal circulation and inhibit its own hepatic metabolism in the fetus, leading to increased DCA concentrations and decreased fetal plasma lactate concentrations during its parenteral administration to the mother. SIGNIFICANCE STATEMENT: This study was the first to administer sodium dichloroacetate (DCA) to pregnant animals (sheep). It showed that DCA administered to the mother can cross the placental barrier and achieve concentrations in fetus sufficient to decrease fetal lactate concentrations. Consistent with findings reported in other species, DCA-mediated inhibition of glutathione transferase zeta1 was also observed in ewes, resulting in reduced metabolism of DCA after prolonged administration.