Quantitative Evaluation of Dichloroacetic Acid Kinetics in Human -- A Physiologically-Based Pharmacokinetic Modeling Investigation

摘要

Dichloroacetic acid (DCA) is a common disinfection byproduct in surface waters and a probable minor metabolite of trichloroethylene. DCA liver carcinogenicity has been demonstrated in rodents but epidemiological evidence in humans is not available. High doses of DCA (10-50 mg/kg) are used to treat metabolic acidosis. Biotransformation of DCA by glutathione transferase zeta (GSTzeta) in the liver is the major elimination pathway in humans. GSTzeta is inactivated by DCA, leading to slower systemic clearance and nonlinear pharmacokinetics after multiple doses. A physiologically-based pharmacokinetic (PBPK) model was developed to quantitatively describe DCA biotransformation and kinetics in humans administered DCA by intravenous infusion and oral ingestion. GSTzeta metabolism was described using a Michaelis-Menten equation coupled with rate constants to account for normal GSTzeta synthesis, degradation, and irreversible covalent binding and inhibition by the glutathione-bound-DCA intermediate. The human DCA PBPK model adequately predicted the DCA plasma kinetics over a 20,000 fold range in administered doses. Apparent inhibition of GSTzeta mediated metabolism of DCA was minimal for low doses of DCA (microgram/kg/day), but was significant for therapeutic doses of DCA. Plasma protein binding of DCA was assumed to be an important factor influencing the kinetics of low doses of DCA (microgram/kg/day). Human equivalent doses (HEDs) were calculated for a 10% increase in mice hepatic liver cancer (2.1 mg/kg/day). The HEDs for the dosimetrics (area under the curve (AUC) for total and free DCA in plasma, AUC of DCA in liver, and amount of DCA metabolized) per day were 0.02, 0.1, 0.1, and 1.0 mg/kg/day, respectively.