Toxicokinetics of bromodichloroacetate in B6C3F1 mice

The oral and i.v. elimination kinetics were investigated for bromodichloroa cetate (BDCA), a haloacetate found in drinking mater. The BDCA was administ ered at a dose of 5, 20 and 100 mg kg(-1) to B6C3F1 mice and appears to dis tribute to the total body water with a mean volume of distribution of 427 /- 79 ml kg(-1). It is subject to first-pass hepatic metabolism with a rang e of bioavailabilities of 0.28-0.73. A mean terminal half-life of 1.37 +/- 0.21 h, was calculated from the two lower doses of both i.v. and oral admin istration. Non-linear behavior was exhibited at doses greater than 20 mg kg (-1), with a much higher than expected area under the curve (AUC), a decrea se in total body clearance (CLb) and an increase in the terminal half-life to 2.3 h at the highest dose. The average CLb was 220 ml h(-1) kg(-1) for t he lower two doses but decreased to 156 ml h(-1) kg(-1) at the high dose. T he BDCA is primarily eliminated by metabolism, with only 2.4% of the parent dose being recovered in the urine at the high dose. The unbound renal clea rance, as calculated from the high dose, was 15.0 ml h(-1) kg(-1). The BDCA is moderately bound to plasma proteins (f(u)= 0.28) and preferentially dis tributes to the plasma with a blood/plasma ratio of 0.88. Copyright (C) 200 1 John Wiley & Sons, Ltd.