Pharmacokinetics and metabolism of dichloroacetate in the F344 rat after prior administration in drinking water.
The effect of prior administration of dichloroacetate (DCA) in drinking 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/liter for 14 days and then challenged with iv bolus iv or gavage doses of [14C1,2]DCA, 16 hr after pretreatment withdrawal. The blood concentration-time profiles of DCA and the disposition of 14C was characterized and compared with controls. The effect of pretreatment on the in vitro metabolism of DCA in hepatic cytosol was also evaluated. Pretreatment caused a significant increase in the blood concentration and AUC0-->infinity of DCA (433.3 versus 2406 microg ml-1 hr). Pharmacokinetic analysis indicated that pretreatment significantly decreased total body clearance (267.4 versus 42.7 ml hr-1 kg-1), which was largely due to decreased metabolism since only modest differences in the urinary clearance of DCA were observed. Pretreatment significantly decreased the formation of 14CO2 after both iv and oral doses of [14C]DCA. The decrease in CO2 formation was also observed after pretreatment with DCA at 0.2 g/liter. Pretreatment also increased the urinary elimination of DCA and several metabolites, particularly glycolate. The in vitro experiments demonstrated that DCA pretreatment inhibited the conversion of DCA to glyoxylate, oxalate, and glycolate in hepatic cytosol. These results indicate that DCA has an auto-inhibitory effect on its metabolism and that pharmacokinetic studies using single doses in naïve rats will underestimate the concentration of DCA at the target tissue during chronic or repeated exposures.
Gonzalez-Leon
A
A
Pharmacology/Toxicology Graduate Program, Washington State University, Pullman, Washington 99164, USA.
Schultz
I R
IR
Xu
G
G
Bull
R J
RJ
D000284:Administration, Oral; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002250:Carbon Radioisotopes; D002849:Chromatography, Gas; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004326:Drinking; D005618:Fresh Water / Q000737:chemistry; D006016:Glycolates / Q000652:urine; D006038:Glyoxylates / Q000652:urine; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010070:Oxalates / Q000652:urine; D051381:Rats; D011916:Rats, Inbred F344
D002250:Carbon Radioisotopes; D006016:Glycolates; D006038:Glyoxylates; D010070:Oxalates; D002245:Carbon Dioxide; D003999:Dichloroacetic Acid; C031150:glyoxylic acid