BJA Advance Access originally published online on January 14, 2005
British Journal of Anaesthesia 2005 94(3):357-365; doi:10.1093/bja/aei058
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Impact of peripheral elimination on the concentration–effect relationship of remifentanil in anaesthetized dogs
1 Faculté de Pharmacie and 2 Faculté de Médecine Vétérinaire, Université de Montréal, Montréal, Québec, Canada
* Corresponding author. E-mail: france.varin{at}umontreal.ca
Background. This study elucidates the impact of sampling site when estimating pharmacokinetic-pharmacodynamic (PK-PD) parameters of drugs such as remifentanil that undergo tissue extraction in the biophase. The interrelationship between the concentrations of remifentanil predicted for the effect compartment and those measured in arterial, venous, and cerebrospinal fluid were investigated under steady-state conditions.
Methods. Following induction of anaesthesia with pentobarbital, an arterial cannula (femoral) and two venous catheters (jugular and femoral) were inserted. Electrodes were placed for EEG recording of theta wave activity. Each dog received two consecutive 5-min infusions for the PK-PD study and a bolus followed by a 60-min infusion was started for the steady-state study. Cerebrospinal fluid, arterial and venous blood samples were drawn simultaneously after 30, 40, and 50 min. At the end of the infusion, arterial blood samples were collected for pharmacokinetic analysis.
Results. Remifentanil PK-PD parameters based on theta wave activity were as follows: apparent volume of distribution at steady-state (Vss) (231±37 ml kg–1), total body clearance (Cl) (63±16 ml min–1 kg–1), terminal elimination half-life (t1/2ß) (7.71 min), effect compartment concentration at 50% of maximal observed effect (EC50) (21±13 ng ml–1), and equilibration rate constant between plasma and effect compartment (ke0) (0.48±0.24 min). The mean steady-state cerebrospinal fluid concentration of 236 ng ml–1 represented 52 and 74% of that in arterial and venous blood, respectively.
Conclusions. Our study re-emphasizes the importance of a sampling site when performing PK-PD modelling for drugs undergoing elimination from the effect compartment. For a drug undergoing tissue elimination such as remifentanil, venous rather than arterial concentrations will reflect more exactly the effect compartment concentrations, under steady-state conditions.
Declaration of interest. Remifentanil was provided by Abbott Laboratories.