PHARMACOKINETICS AND PHARMACODYNAMICS OF REMIFENTANIL IN VOLUNTEER SUBJECTS WITH SEVERE LIVER-DISEASE

Background: Remifentanil, a new p-opioid agonist with an extremely sho rt duration of action, is metabolized by circulating and tissue estera ses; therefore, its clearance should be relatively unaffected by chang es in hepatic or renal function. This study was designed to determine whether severe hepatic disease affects the pharmacokinetics or pharmac odynamics of remifentanil. Methods: Ten volunteers with chronic, stabl e, severe hepatic disease and awaiting liver transplantation and ten m atched controls were enrolled. Each subject was given a 4-h infusion o f remifentanil. The first five pairs received 0.0125 mu g . kg(-1). mi n(-1) for 1 h followed by 0.025 mu g . kg(-1). min(-1) for 3 h; the se cond five pairs received double these Infusion rates. During and after the infusion, arterial blood was obtained for pharmacokinetic analyse s, and the ventilatory response to a hypercarbic challenge was assesse d. Simultaneous pharmacokinetic and pharmacodynamic analyses were perf ormed. The pharmacokinetics were described using a one-compartment int ravenous infusion model, and ventilatory depression was modelled using the inhibitory E(max) model. The pharmacokinetics of the metabolite G R90291 were determined using noncompartmental methods. Results: There were no differences in any of the pharmacokinetic parameters for remif entanil or GR90291 between the two groups, The subjects with liver dis ease were more sensitive to the ventilatory depressant effects of remi fentanil. The EC(50) values (the remifentanil concentrations determine d from simultaneous pharmacokinetic/pharmacodynamic analyses to depres s carbon dioxide-stimulated minute ventilation by 50%) in the control and hepatic disease groups were 2.52 ng/ml(95% confidence interval 2.0 7-2.97 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. S uch patients may be more sensitive to the ventilatory depressant effec ts of remifentanil, a finding of uncertain clinical significance, cons idering the extremely short duration of action of the drug.