Pharmacokinetics and pharmacodynamics of dichloroacetate in patients with cirrhosis

Objectives: We tested the hypotheses that (1) plasma clearance of dichloroa cetate is decreased in patients with end-stage cirrhosis, and (2) patients with cirrhosis are vulnerable to dichloroacetate-induced hypoglycemia cause d 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-H-2(2)-glucose, After a 2-hour bas al period, subjects received intravenous dichloroacetate, 35 mg/kg, over 30 minutes. Dichloroacetate pharmacokinetics were compared by the mixed-effec ts population-based technique. Glucose production was calculated by means o f isotope dilution. Results: The optimal dichloroacetate pharmacokinetic model for both subject s with cirrhosis and control subjects had two compartments, with all parame ters weight normalized. Peak plasma dichloroacetate concentration in subjec ts with cirrhosis did not differ from that in control subjects, but typical dichloroacetate clearance was only 36% of that in control subjects (P < .0 01). Dichloroacetate decreased plasma lactate concentration by similar to 5 0% (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 c ontrol subjects. Dichloroacetate-induced decreases in plasma lactate and gl ucose concentrations and in glucose production in subjects with cirrhosis d id not differ from those in control subjects. Conclusions: Plasma dichloroacetate clearance is markedly decreased in pati ents with cirrhosis, likely because of compromised hepatic function. Subjec ts with cirrhosis exhibit neither exaggerated inhibition of glucose product ion nor increased risk of hypoglycemia as a result of acute dichloroacetate -induced hypolactatemia.