Quantitative evaluation of dichloroacetic acid kinetics in human—a physiologically based pharmacokinetic modeling investigation

Abstract

Dichloroacetic acid is a common disinfection by-product in surface waters and is a probable minor metabolite of trichloroethylene. Dichloroacetic acid (DCA) liver carcinogenicity has been demonstrated in rodents but epidemiological evidence in humans is not available. High doses of DCA (∼50 mg/kg) are used clinically to treat metabolic acidosis. Biotransformation of DCA by glutathione transferase zeta (GSTzeta) in the liver is the major elimination pathway in humans. GSTzeta is also 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. With some departures between observation and model prediction, 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 (μg/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 (μg/kg day). Polymorphisms of GSTzeta may help explain inter-individual variability in DCA plasma kinetics and warrants evaluation. In conclusion, using a previously published rodent DCA PBPK model (Keys, D.A., Schultz, I.R., Mahle, D.A., Fisher, J.W., 2004. A quantitative description of suicide inhibition of dichloroacetic acid in rats and mice. Toxicol. Sci. 82, 381–393) and this human DCA PBPK model, 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-concentration-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. Research on the mechanism of action of DCA and the relevance of mouse liver cancer is needed to better understand which dosimetric may be appropriate for extrapolation from animal studies to human.