title: Pharmacokinetics of oral dichloroacetate in dogs.
abstract: We characterized the pharmacokinetics and dynamics of dichloroacetate (DCA), an investigational drug for mitochondrial diseases, pulmonary arterial hypertension, and cancer. Adult Beagle dogs were orally administered 6.25 mg/kg q12h DCA for 4 weeks. Plasma kinetics was determined after 1, 14, and 28 days. The activity and expression of glutathione transferase zeta 1 (GSTZ1), which biotransforms DCA to glyoxylate, were determined from liver biopsies at baseline and after 27 days. Dogs demonstrate much slower clearance and greater inhibition of DCA metabolism and GSTZ1 activity and expression than rodents and most humans. Indeed, the plasma kinetics of DCA in dogs is similar to humans with GSTZ1 polymorphisms that confer exceptionally slow plasma clearance. Dogs may be a useful model to further investigate the toxicokinetics and therapeutic potential of DCA.
authors.affiliation: Small Animal Clinical Sciences, University of Florida, Gainesville, FL, 32610, USA. maisenbacherh@ufl.edu.
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Maisenbacher
authors.forename: Albert L
authors.initials: AL
authors.lastname: Shroads
authors.forename: Guo
authors.initials: G
authors.lastname: Zhong
authors.forename: Adam D
authors.initials: AD
authors.lastname: Daigle
authors.forename: Monica M
authors.initials: MM
authors.lastname: Abdelmalak
authors.forename: Ivan Sosa
authors.initials: IS
authors.lastname: Samper
authors.forename: Brandy D
authors.initials: BD
authors.lastname: Mincey
authors.forename: Margaret O
authors.initials: MO
authors.lastname: James
authors.forename: Peter W
authors.initials: PW
authors.lastname: Stacpoole
mesh_terms: D000096:Acetone / Q000031:analogs & derivatives / Q000652:urine; D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D015153:Blotting, Western; D003999:Dichloroacetic Acid / Q000097:blood / Q000493:pharmacokinetics*; D004285:Dogs; D005982:Glutathione Transferase / Q000378:metabolism; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D008298:Maleates / Q000652:urine; D014443:Tyrosine / Q000378:metabolism; D019745:cis-trans-Isomerases / Q000378:metabolism
chemical_list: D008298:Maleates; C460372:maleylacetone; D000096:Acetone; D014443:Tyrosine; D003999:Dichloroacetic Acid; D005982:Glutathione Transferase; D019745:cis-trans-Isomerases; C021531:maleylacetoacetate isomerase
keywords: Drug Development; Mitochondrial Diseases; Pharmacodynamics; Pharmacokinetics