These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: Low-dose pharmacokinetics and oral bioavailability of dichloroacetate in naive and GST-zeta-depleted rats.
    Author: Saghir SA, Schultz IR.
    Journal: Environ Health Perspect; 2002 Aug; 110(8):757-63. PubMed ID: 12153755.
    Abstract:
    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 (less 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.
    [Abstract] [Full Text] [Related] [New Search]