Pharmacokinetics of dichloroacetate in patients undergoing liver transplantation

Robert Shangraw, Dennis M. Fisher

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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 · kg -1 · 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.

Original languageEnglish (US)
Pages (from-to)851-858
Number of pages8
JournalAnesthesiology
Volume84
Issue number4
DOIs
StatePublished - Apr 1996

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Liver Transplantation
Pharmacokinetics
Liver
End Stage Liver Disease
Lactic Acidosis
Plasma Volume
Bicarbonates
Gas Chromatography
Mass Spectrometry
Homeostasis
Anesthesia
Acids
Population

Keywords

  • Dichloroacetate
  • Liver: disease; transplantation
  • Pharmacokinetic modeling: NONMEM; population techniques

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Pharmacokinetics of dichloroacetate in patients undergoing liver transplantation. / Shangraw, Robert; Fisher, Dennis M.

In: Anesthesiology, Vol. 84, No. 4, 04.1996, p. 851-858.

Research output: Contribution to journalArticle

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abstract = "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 · kg -1 · 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.",
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N2 - 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 · kg -1 · 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.

AB - 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 · kg -1 · 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.

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