Pharmacokinetics of dichloroacetate in patients undergoing liver transplantation.
BACKGROUND
Dichloroacetate (DCA) is an effective alternative to bicarbonate to treat lactic acidosis and stabilize acid-base homeostasis during liver transplantation. Although DCA presumably is metabolized by the liver, the impact of end-stage liver disease and liver transplantation on DCA distribution and elimination is unknown. Therefore, the pharmacokinetics of DCA were determined in patients with end-stage liver disease undergoing orthotopic liver transplantation.


METHODS
Thirty-three patients undergoing liver transplantation were given DCA as two 40-mg/kg infusions over 60 min, the first after induction of anesthesia, the second 4 h later. Plasma DCA concentrations were determined by gas chromatography-mass spectroscopy. One- and two-compartment pharmacokinetic models were fitted to DCA concentrations versus time data using a mixed-effects population approach. Various models permitted changes in central compartment volume and/or plasma clearance to account for changes in hepatic mass and function and circulatory status during the paleohepatic, anhepatic, and neohepatic periods.


RESULTS
The optimal model had two compartments. DCA clearance was 0.997, 0.0, and 1.69 ml x kg(-1) x min(-1) during the paleohepatic, anhepatic, and neohepatic periods, respectively (P < 0.05). Interindividual variability in central compartment volume differed during the paleohepatic and neohepatic periods. There was no apparent influence of blood or fluid requirements during surgery on DCA clearance or volume of distribution.


CONCLUSIONS
Absence of DCA clearance during the anhepatic period indicates that DCA is metabolized exclusively by the liver. Differences in interindividual variability in central compartment volume during the paleohepatic and neohepatic periods possibly result from physiologic changes during surgery. Finally, the results indicate that the newly transplanted liver eliminates DCA better than the native liver.
Shangraw
R E
RE
Department of Anesthesiology, Oregon Health Sciences University, Portland 97201-3098, USA.
Fisher
D M
DM
D003999:Dichloroacetic Acid / Q000493:pharmacokinetics*; D006801:Humans; D016031:Liver Transplantation; D008657:Metabolic Clearance Rate; D008954:Models, Biological
D003999:Dichloroacetic Acid