Vol. 26, Issue 11, 1134-1143, November 1998

Pharmacokinetics and Metabolism of [¹⁴C]Dichloroacetate in Male Sprague-Dawley Rats
Identification of Glycine Conjugates, Including Hippurate, as Urinary Metabolites of Dichloroacetate

Margaret O. James, Zimeng Yan,¹ Rachel Cornett, V. Murali K. M. Jayanti,² George N. Henderson, Natalia Davydova, Michael J. Katovich, Brad Pollock, and Peter W. Stacpoole

Departments of Medicinal Chemistry (MOJ, RC, VMKMJ) and Pharmacodynamics (MJK), College of Pharmacy, and Department of Medicine, Division of Endocrinology and Metabolism (ZY, GNH, ND, PWS), Department of Health Policy and Epidemiology (BP), and Department of Biochemistry and Molecular Biology (PWS), College of Medicine, University of Florida

Pathways of metabolism of dichloroacetate (DCA), an investigational drug for the treatment of lactic acidosis in humans and a rodent hepatocarcinogen, are poorly understood. In this study, rats were given, by gavage, one or two 50 mg/kg doses of NaDCA. DCA labeled with ¹⁴C (carboxy carbon) or ¹³C (both carbons) was used in studies of disposition and pharmacokinetics, respectively. The effect of fasting for 14 hr before dosing was studied. Expired air, urine, feces, and tissues were collected from [¹⁴C]DCA-dosed rats. Urine was analyzed by HPLC, GC/MS, and NMR spectroscopy. Plasma samples were analyzed by GC/MS. DCA plasma elimination half-lives were 0.1 ± 0.02 and 5.4 ± 0.8 hr in young 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 CO₂ varied from 17 to 46% and was lower (p < 0.001) in fed rats, compared with rats fasted overnight before dosing. Urine contained DCA and DCA metabolites, including oxalate, glyoxylate, and conjugated glycine (mainly hippurate and phenylacetylglycine). More unchanged DCA was excreted by large rats pretreated with DCA (mean, 20.2% of the dose) than by young adult rats given one dose of DCA (mean, 0.5%). This study confirmed that CO₂, glycine, and oxalate are major products of DCA metabolism, it demonstrated that one dose of DCA altered the elimination of a subsequent dose, and it showed that age or body size, as well as access to food, significantly affected DCA metabolism in rats.