Low-Dose Pharmacokinetics and Oral Bioavailability of Dichloroacetate in Naive and GST-zeta Depleted Rats
- ASSOC WESTERN UNIVERSITY
- BATTELLE (PACIFIC NW LAB)
Pharmacokinetics of dichloroacetate (DCA) in naive and glutathione-S-transferase-zeta (GSTzeta) depleted rats was studied at doses approaching human daily exposure levels. In vitro metabolism of DCA by rat and human liver cytosol was also compared. Jugular vein cannulated male Fischer-344 rats were administered (i.v or gavage) with graded doses of DCA ranging from 0.05-20 mg/kg and time-course blood samples collected from the cannula. GSTzeta was depleted by exposing rats to DCA (0.2 g/L DCA) in drinking water for 7 days. Elimination of DCA by naive rats was so rapid that only the 1-20 mg/kg i.v. and 5 and 20 mg/kg gavage doses provided plasma concentrations above the method detection limit. GSTzeta 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 GSTzeta depleted rats, the pharmacokinetics became line ar at doses No.1 mg/kg. All oral doses were rapidly absorbed without any lag time. At higher oral doses (?5 mg/kg in GSTzeta depleted and?20 mg/kg in naive), secondary peaks in the plasma concentration appeared long after the completion of the initial absorption phase. Virtually all the dose was eliminated through metabolic clearance; the rate of urinary elimination of DCA was < 1 ml h-1kg-1. A maximum of 1.0?0.3% dose was recovered in urine within 24 h in the GSTzeta depleted rats dosed i.v. with 20 mg/kg. The rate of in vitro metabolism of DCA by human cytosol was statistically similar to the GSTzeta depleted rats (p > 0.3), which supported the use of GSTzeta depleted rats as a model for assessing kinetics of DCA in humans. Oral bioavailability of DCA was 0-13% in naive and 14-75% in GSTzeta depleted rats. Oral bioavailability of DCA to humans through consumption of drinking water was predicted to be a maximum of 0.05%.
- Research Organization:
- Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
- Sponsoring Organization:
- US Department of Energy (US)
- DOE Contract Number:
- AC06-76RL01830
- OSTI ID:
- 15001581
- Report Number(s):
- PNWD-SA-5424; TRN: US200406%%28
- Journal Information:
- Environmental Health Perspectives, Vol. 110, Issue 8; Other Information: PBD: 1 Jan 2002
- Country of Publication:
- United States
- Language:
- English
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