PHARMACOKINETICS AND METABOLISM OF DICHLOROACETATE IN THE F344 RAT AFTER PRIOR ADMINISTRATION IN DRINKING-WATER

The effect of prior administration of dichloroacetate (DCA) in drinkin g water on the pharmacokinetics of DCA in male F344 rats was studied. Rats were provided with DCA in their drinking water at 0.2 and 2.0 g/l iter for 14 days and then challenged with iv bolus iv or gavage doses of [Cl-14(1,2)]DCA, 16 hr after pretreatment withdrawal. The blood con centration-time profiles of DCA and the disposition of C-14 was charac terized and compared with controls. The effect of pretreatment on the in vitro metabolism of DCA in hepatic cytosol was also evaluated. Pret reatment caused a significant increase in the blood concentration and AUC(0-->infinity) of DCA (433.3 versus 2406 mu g ml(-1) hr). Pharmacok inetic analysis indicated that pretreatment significantly decreased to tal body clearance (267.4 versus 42.7 mi hr(-1) kg(-1)), which was lar gely due to decreased metabolism since only modest differences in the urinary clearance of DCA were observed. Pretreatment significantly dec reased the formation of (CO2)-C-14 after both iv and oral doses of [C- 14]DCA. The decrease in CO2 formation was also observed after pretreat ment with DCA at 0.2 g/liter. Pretreatment also increased the urinary elimination of DCA and several metabolites, particularly glycolate. Th e in vitro experiments demonstrated that DCA pretreatment inhibited th e conversion of DCA to glyoxylate, oxalate, and glycolate in hepatic c ytosol. These results indicate that DCA has an auto-inhibitory effect on its metabolism and that pharmacokinetic studies using single doses in naive rats will underestimate the concentration of DCA at the targe t tissue during chronic or repeated exposures. (C) 1997 Academic Press .