Pharmacokinetics and pharmacodynamics of dichloroacetate in patients with cirrhosis

Robert E. Shangraw, Dennis M. Fisher

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Objectives: We tested the hypotheses that (1) plasma clearance of dichloroacetate is decreased in patients with end-stage cirrhosis, and (2) patients with cirrhosis are vulnerable to dichloroacetate-induced hypoglycemia caused by exaggerated inhibition of hepatic glucose production. Methods: Seven subjects with cirrhosis and six healthy volunteers received a 5-hour primed constant infusion of 6,6-2H2-glucose. After a 2-hour basal period, subjects received intravenous dichloroacetate, 35 mg/kg, over 30 minutes. Dichloroacetate pharmacokinetics were compared by the mixed-effects population-based technique. Glucose production was calculated by means of isotope dilution. Results: The optimal dichloroacetate pharmacokinetic model for both subjects with cirrhosis and control subjects had two compartments, with all parameters weight normalized. Peak plasma dichloroacetate concentration in subjects with cirrhosis did not differ from that in control subjects, but typical dichloroacetate clearance was only 36% of that in control subjects (P < .001). Dichloroacetate decreased plasma lactate concentration by ~50% (P < .001), glucose production by 7% to 9% (P < .05), and plasma glucose concentration by 9% to 14% (P < .05) in both subjects with cirrhosis and control subjects. Dichloroacetate-induced decreases in plasma lactate and glucose concentrations and in glucose production in subjects with cirrhosis did not differ from those in control subjects. Conclusions: Plasma dichloroacetate clearance is markedly decreased in patients with cirrhosis, likely because of compromised hepatic function. Subjects with cirrhosis exhibit neither exaggerated inhibition of glucose production nor increased risk of hypoglycemia as a result of acute dichloroacetate-induced hypolactatemia.

Original languageEnglish (US)
Pages (from-to)380-390
Number of pages11
JournalClinical pharmacology and therapeutics
Volume66
Issue number4
DOIs
StatePublished - Nov 1 1999

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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