PHARMACOKINETICS AND METABOLISM OF [C-14]DICHLOROACETATE IN MALE SPRAGUE-DAWLEY RATS - IDENTIFICATION OF GLYCINE CONJUGATES, INCLUDING HIPPURATE, AS URINARY METABOLITES OF DICHLOROACETATE

Pathways of metabolism of dichloroacetate (DCA), an investigational dr ug for the treatment of lactic acidosis in humans and a rodent hepatoc arcinogen, are poorly understood. In this study, rats were given, by g avage, one or two 50 mg/kg doses of NaDCA. DCA labeled with C-14 (carb oxy carbon) or C-13 (both carbons) was used in studies of disposition and pharmacokinetics, respectively. The effect of fasting for 14 hr be fore dosing was studied. Expired air, urine, feces, and tissues were c ollected from [C-14]DCA-dosed rats. Urine was analyzed by HPLC, GC/MS, and NMR spectroscopy. Plasma samples were analyzed by GC/MS. DCA plas ma elimination half-lives were 0.1 +/- 0.02 and 5.4 +/- 0.8 hr in youn g adult rats (180-265 g, 3-4 months of age) given one or two doses of DCA, respectively, and 9.7 +/- 1 hr in large, 16-month-old rats given two DCA doses. The percentage of the DCA dose excreted as CO, varied f rom 17 to 46% and was lower (p < 0.001) in fed rats, compared with rat s fasted overnight before dosing. Urine contained DCA and DCA metaboli tes, including oxalate, glyoxylate, and conjugated glycine (mainly hip purate and phenylacetylglycine). More unchanged DCA was excreted by la rge rats pretreated with DCA (mean, 20.2% of the dose) than by young a dult rats given one dose of DCA (mean, 0.5%). This study confirmed tha t CO2, glycine, and oxalate are major products of DCA metabolism, it d emonstrated that one dose of DCA altered the elimination of a subseque nt dose, and it showed that age or body size, as well as access to foo d, significantly affected DCA metabolism in rats.