The extent of dichloroacetate formation from trichloroethylene, chloral hydrate, trichloroacetate, and trichloroethanol in B6C3F1 mice.
Conflicting data have been published related to the formation of dichloroacetate (DCA) from trichloroethylene (TRI), chloral hydrate (CH), or trichloroacetic acid (TCA) in B6C3F1 mice. TCA is usually indicated as the primary metabolic precursor to DCA. Model simulations based on the known pharmacokinetics of TCA and DCA predicted blood concentrations of DCA that were 10- to 100-fold lower than previously published reports. Because DCA has also been shown to form as an artifact during sample processing, we reevaluated the source of the reported DCA, i.e., whether it was metabolically derived or formed as an artifact. Male B6C3F1 mice were dosed with TRI, CH, trichloroethanol (TCE), or TCA and metabolic profiles of each were determined. DCA was not detected in any of these samples above the assay LOQ of 1.9 microM of whole blood. In order to slow the clearance of DCA, mice were pretreated for 2 weeks with 2 g/liter of DCA in their drinking water. Even under this pretreatment condition, no DCA was detected from a 100 mg/kg i.v. dose of TCA. Although there is significant uncertainty in the amount of DCA that could be generated from TRI or its metabolites, our experimental data and pharmacokinetic model simulations suggest that DCA is likely formed as a short-lived intermediate metabolite. However, its rapid elimination relative to its formation from TCA prevents the accumulation of measurable amounts of DCA in the blood.
Merdink
J L
JL
Graduate Program in Pharmacology/Toxicology, Washington State University, Pullman 99164, USA. jl_merdink@pnl.gov
Gonzalez-Leon
A
A
Bull
R J
RJ
Schultz
I R
IR
D000818:Animals; D001682:Biological Availability; D002697:Chloral Hydrate / Q000493:pharmacokinetics*; D003999:Dichloroacetic Acid / Q000097:blood / Q000378:metabolism*; D005023:Ethylene Chlorohydrin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006207:Half-Life; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008954:Models, Biological; D014238:Trichloroacetic Acid / Q000493:pharmacokinetics*; D014241:Trichloroethylene / Q000493:pharmacokinetics*
D014241:Trichloroethylene; D002697:Chloral Hydrate; D014238:Trichloroacetic Acid; D005023:Ethylene Chlorohydrin; D003999:Dichloroacetic Acid; C005849:2,2,2-trichloroethanol