Low-Dose Pharmacokinetics and Oral Bioavailability of Dichloroacetate in Naive and GST[zeta]-Depleted Rats. (Articles)

Article excerpt

We studied the pharmacokinetics of dichloroacetate (DCA) in naive rats and rats depleted of glutathione S-transferase-zeta (GST[zeta]), 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. GST[zeta] 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. GST[zeta] 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 GST[zeta]-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 ([greater than or equal to] 5 mg/kg in GST[zeta]-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 GST[zeta]-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 GST[zeta]-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 GST[zeta]-depleted rat liver cytosol. Key words: animal study, dichloroacetic acid, drinking water disinfection by-products, halogenated acetic acids, human risk assessment, human in vitro metabolism, low-dose pharmacokinetics, oral bioavailability, rat in vitro metabolism, toxicology. Environ Health Perspect 110:757-763 (2002). [Online 13 June 2002]



Dichloroacetate (DCA) is a drinking water disinfectant by-product commonly identified in municipal water supplies. Concentrations of DCA in finished drinking water have been reported as high as 133 [micro]g/L (1), although concentrations < 25 [micro]g/L are more common (2,3). DCA is a metabolite of certain chlorinated industrial solvents and of several pharmaceuticals (4). DCA has also been used for decades as an investigational drug to treat numerous cardiovascular and metabolic disorders in humans, for example, diabetes, hypercholesterolemia, and amelioration of lactic acid during liver transplantation (4-6). Recently, DCA has been used in clinical trials to treat congenital or acquired lactic acidosis in children (5,7). Human exposure to DCA ranges from ~1 to 4 [micro]/kg/day through consumption of drinking water and up to 50 mg/kg/day from the use of DCA as a therapeutic drug (4).

DCA is rapidly and completely absorbed from the gastrointestinal (GI) tract and is extensively metabolized both in rodents and in humans, with glyoxylate, oxalate, glycolate, and C[O.sub.2] being the major metabolites (8,9). Only a small percentage (< 3%) of the dose is excreted as the parent compound (8-10). DCA metabolism occurs primarily in the liver (11), mediated through a recently characterized class of glutathione S-transferase, GST[zeta] (GSTZ1-1) (12). DCA is also a mechanism-based inhibitor of GST[zeta], and prolonged exposure to DCA in rodents causes both reduction in metabolism and depletion of immunoreactive GST[zeta] protein levels from the liver (9,13-15). …