Accession Number:

ADA520755

Title:

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

Descriptive Note:

Interim rept. for Jan-Dec 2007

Corporate Author:

HUMAN EFFECTIVENESS DIRECTORATE WRIGHT-PATTERSON AFB OH APPLIED BIOTECHNOLOGY BRANCH

Report Date:

2008-01-01

Pagination or Media Count:

49.0

Abstract:

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 mgkg 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 microgramkgday, 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 microgramkgday. Human equivalent doses HEDs were calculated for a 10 increase in mice hepatic liver cancer 2.1 mgkgday. 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 mgkgday, respectively.

Subject Categories:

  • Biochemistry
  • Toxicology
  • Pharmacology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE