TY - JOUR T1 - <strong>Pharmacokinetic and biochemical profiling of Sodium Dichloroacetate in pregnant ewes and fetuses</strong> JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.120.000330 SP - DMD-AR-2020-000330 AU - Serene Joseph AU - Abhisheak Sharma AU - Lloyd P. Horne AU - Charles E. Wood AU - Taimour Langaee AU - Margaret O. James AU - Peter W. Stacpoole AU - Maureen Keller-Wood Y1 - 2021/01/01 UR - http://dmd.aspetjournals.org/content/early/2021/04/01/dmd.120.000330.abstract N2 - 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 activates the pyruvate dehydrogenase complex (PDC) to increase energy production and decrease circulating lactate concentrations. In a sheep model of chronic hypercortisolemia in pregnancy, PDK4 mRNA was increased and fetal bradycardia was evident at birth in the affected fetuses. The current study shows DCA crosses the placenta and can be measured in fetal blood, following its intravenous administration to pregnant ewes during late gestation and in labor. Sustained administration of DCA to the mother over 72h decreased the hepatic expression of the DCA-metabolizing enzyme GSTZ1 in the fetuses exposed to the drug, leading to higher fetal plasma DCA concentrations during continued dosing, and reduced plasma lactate levels. Multi-compartmental pharmacokinetics modeling indicated drug metabolism in the fetal and maternal compartments is best described by the autoinhibition of metabolism in both compartments. We provide the first evidence that DCA can cross the placental compartment to enter the fetal circulation, inhibit its own hepatic metabolism and decrease fetal plasma lactate concentrations. 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 to decrease the fetal lactate concentrations. Like other reported species, DCA mediated inhibition of GSTZ1 was also observed in ewes which resulted in the reduced metabolism of DCA after a prolonged administration. ER -