Low-dose pharmacokinetics and oral bioavailability of dichloroacetate in naive and GSTζ-depleted rats

We studied the pharmacokinetics of dichloroacetate (DCA) in naive rats and rats depleted of glutathione S-transferase-zeta (GSTzeta), at doses approaching human daily exposure levels. We also compared in vitro metabolism of DCA by rat and human liver cytosol. Jugular vein-cannulated male Fischer-344 rats received graded doses of DCA ranging from 0.05 to 20 mg/kg (intravenously or by gavage), and we collected time-course blood samples from the cannulas. GSTzeta activity was depleted by exposing rats to 0.2 g/L DCA in drinking water for 7 days before initiation of pharmacokinetic studies. Elimination of DCA by naive rats was so rapid that only 1-20 mg/kg intravenous and 5 and 20 mg/kg gavage doses provided plasma concentrations above the method detection limit of 6 ng/mL. GSTzeta depletion slowed DCA elimination from plasma, allowing kinetic analysis of doses as low as 0.05 mg/kg. DCA elimination was strongly dose dependent in the naive rats, with total body clearance declining with increasing dose. In the GSTzeta-depleted rats, the pharmacokinetics became linear at doses less than or equal to 1 mg/kg. Virtually all of the dose was eliminated through metabolic clearance; the rate of urinary elimination was < 1 mL/hr/kg. At higher oral doses (≥ 5 mg/kg in GSTζ-depleted and 20 mg/kg in naive rats), secondary peaks in the plasma concentration appeared long after the completion of the initial absorption phase. Oral bioavailability of DCA was 0-13% in naive and 14-75% in GSTζ-depleted rats. Oral bioavailability of DCA in humans through consumption of drinking water was predicted to be very low and < 1%. The use of the GSTzeta-depleted rat as a model for assessing the kinetics of DCA in humans is supported by the similarity in pharmacokinetic parameter estimates and rate of in vitro metabolism of DCA by human and GSTzeta-depleted rat liver cytosol.