Pharmacokinetics and metabolism of dichloroacetate in the F344 rat after prior administration in drinking water

Journal Article · Tue Oct 14 04:00:00 EDT 1997 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1006/taap.1997.8232· OSTI ID:1599094

Gonzalez-Leon, Alberto ^[1]; Schultz, Irvin R. ^[2]; Xu, Gui H. ^[1]; Bull, Richard J. ^[3]

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1. Washington State University Tri-Cities
2. BATTELLE (PACIFIC NW LAB)
3. SELF-EMPLOYED CONSULTANTS

The effect of chronic administration of dichloroacetate (DCA) in drinking water on the pharmacokinetics of DCA in male F344 rats was studied. Rats were provided with DCA in their drinking water at 0.2 and 2.0 g/l for 14 days and then given i.v. or gavage doses of 14C-DCA. The blood concentration-time profile of DCA and the disposition of 14C was characterized and compared with control rats. Additional experiments studied the effect of pretreatment on the in-vitro metabolism of DCA in hepatic cytosol. Pretreatment caused a significant increase in the blood concentration and AUCof DCA (433.3 vs. 2406 g ml-1 hr). Pharmacokinetic analysis indicated that pretreatment caused a significant decrease in total body clearance (267.4 vs. 42.7 ml hr-1 kg-1) which was largely due to decreased metabolism because only modest differences in the urinary clearance of DCA were observed. Pretreatment significantly decreased the formation of 14C-CO2 after both i.v. and oral doses of 14C-DCA. The decrease in CO2 formation was also observed after pretreatment with DCA at 0.2 g/l. Pretreatment increased the urinary elimination of DCA and several metabolites, especially glycollate. The results of the in-vitro experiments were consistent with the conclusion that DCA was inhibiting its metabolism as pretreatment significantly reduced the formation of glyoxylate-oxalate-glycollate in hepatic cytosol. These results indicate that DCA has an auto-inhibitory effect on its metabolism and that previous pharmacokinetic studies using single doses in naive rats may underestimate the elimination of DCA during chronic or repeated exposures.

• Research Organization: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC05-76RL01830
• OSTI ID: 1599094
• Report Number(s): PNWD-SA-5221
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 146
• Country of Publication: United States
• Language: English