Pharmacokinetics and pharmacodynamics of remifentanil in volunteer subjects with severe liver disease

Background: Remifentanil, a new p-opioid agonist with an extremely short duration of action, is metabolized by circulating and tissue esterases; therefore, its clearance should be relatively unaffected by changes in hepatic or renal function. This study was designed to determine whether severe hepatic disease affects the pharmacokinetics or pharmacodynamics of remifentanil. Methods: Ten volunteers with chronic, stable, severe hepatic disease and awaiting liver transplantation and ten matched controls were enrolled. Each subject was given a 4-h infusion of remifentanil. The first five pairs received 0.0125 mu g . kg(-1). min(-1) for 1 h followed by 0.025 mu g . kg(-1). min(-1) for 3 h; the second five pairs received double these Infusion rates. During and after the infusion, arterial blood was obtained for pharmacokinetic analyses, and the ventilatory response to a hypercarbic challenge was assessed. Simultaneous pharmacokinetic and pharmacodynamic analyses were performed. The pharmacokinetics were described using a one-compartment intravenous infusion model, and ventilatory depression was modelled using the inhibitory E(max) model. The pharmacokinetics of the metabolite GR90291 were determined using noncompartmental methods. Results: There were no differences in any of the pharmacokinetic parameters for remifentanil or GR90291 between the two groups, The subjects with liver disease were more sensitive to the ventilatory depressant effects of remifentanil. The EC(50) values (the remifentanil concentrations determined from simultaneous pharmacokinetic/pharmacodynamic analyses to depress carbon dioxide-stimulated minute ventilation by 50%) in the control and hepatic disease groups were 2.52 ng/ml(95% confidence interval 2.07-2.97 ng/ml) and 1.56 ng/ml(9596 confidence interval 1.37-1.76 ng/ml), respectively. Conclusions: The pharmacokinetics of remifentanil and GR90291 are unchanged In persons with severe, chronic liver disease. Such patients may be more sensitive to the ventilatory depressant effects of remifentanil, a finding of uncertain clinical significance, considering the extremely short duration of action of the drug.