title: Pharmacokinetics and pharmacodynamics of remifentanil in volunteer subjects with severe liver disease.
abstract: BACKGROUND
  Remifentanil, a new mu-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 microgram x kg(-1) x min(-1) for 1 h followed by 0.025 microgram x kg(-1) x 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 (95% 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.
authors.affiliation: Department of Anesthesia, Massachusetts General Hospital and Harvard Medical School, Boston, USA. dershwitz@etherdome.mgh.harvard.edu
authors.forename: M
authors.initials: M
authors.lastname: Dershwitz
authors.forename: J F
authors.initials: JF
authors.lastname: Hoke
authors.forename: C E
authors.initials: CE
authors.lastname: Rosow
authors.forename: P
authors.initials: P
authors.lastname: Michałowski
authors.forename: P M
authors.initials: PM
authors.lastname: Connors
authors.forename: K T
authors.initials: KT
authors.lastname: Muir
authors.forename: J L
authors.initials: JL
authors.lastname: Dienstag
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077208:Remifentanil
chemical_list: D000701:Analgesics, Opioid; D010880:Piperidines; C084032:GI 90291; D000077208:Remifentanil