In vivo kinetics of trichloroacetate in male Fischer 344 rats

Trichloroacetate (TCA) is a toxicologically important metabolite of the industrial solvents trichloroethylene and tetrachloroethylene, and a by-product of the chlorination of drinking water. Tissue disposition and elimination of 14C-TCA were investigated in male Fischer 344 rats injected iv with 6.1, 61, or 306 micromol TCA/kg body weight. Blood and tissues were collected at various time points up to 24 h. No metabolites were observed in plasma, urine, or tissue extracts. Overall TCA kinetics in tissues were similar at all doses. Based on similar terminal elimination rate constants, tissues could be divided into three classes: plasma, RBC, muscle, and fat; kidney and skin; and liver, small intestine, and large intestine. Nonextractable radiolabel, assumed to be biologically incorporated metabolites in both liver and plasma, increased with time, peaking at 6-9 h postinjection. The fraction of the initial dose excreted in the urine at 24 h increased from 67% to 84% as the dose increased, whereas fecal excretion decreased from 7% to 4%. The cumulative elimination of TCA as CO2 at 24 h decreased from 12% to 8% of the total dose. Two important kinetic processes were identified: a) hepatic intracellular concentrations of TCA were significantly greater than free plasma concentrations, indicating concentrative transport at the hepatic sinusoidal plasma membrane, and b) TCA appears to be reabsorbed from urine postfiltration at the glomerulus, either in the renal tubules or in the bladder. These processes have an impact on the effective tissue dosimetry in liver and kidney and may play an important role in TCA toxicity.