Mixed-effects modeling of the influence of alfentanil on propofol pharmacokinetics.
BACKGROUND
The influence of alfentanil on the pharmacokinetics of propofol is poorly understood. Therefore, the authors studied the effect of a pseudo-steady state concentration of alfentanil on the pharmacokinetics of propofol.


METHODS
The pharmacokinetics of propofol were studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While volunteers breathed 30% O2 in air, 1 mg/kg intravenous propofol was given in 1 min, followed by 3 mg.kg(-1).h(-1) for 59 min (sessions A and B). During session B, a target-controlled infusion of alfentanil (target concentration, 80 ng/ml) was given from 10 min before the start until 6 h after termination of the propofol infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the blood propofol and plasma alfentanil concentration were collected until 6 h after termination of the propofol infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of alfentanil and hemodynamic parameters on propofol pharmacokinetics were constructed.


RESULTS
A two-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of propofol. Alfentanil decreased the elimination clearance of propofol from 2.1 l/min to 1.9 l/min, the distribution clearance from 2.7 l/min to 2.0 l/min, and the peripheral volume of distribution from 179 l to 141 l. Scaling the pharmacokinetic parameters to cardiac output, heart rate, and plasma alfentanil concentration significantly improved the model.


CONCLUSIONS
Alfentanil alters the pharmacokinetics of propofol. Cardiac output and heart rate have an important influence on the pharmacokinetics of propofol.
Mertens
Martijn J
MJ
Department of Anesthesiology, Leiden University Medical Center, The Netherlands.
Olofsen
Erik
E
Burm
Anton G L
AG
Bovill
James G
JG
Vuyk
Jaap
J
D000328:Adult; D015760:Alfentanil / Q000494:pharmacology*; D018686:Anesthetics, Intravenous / Q000493:pharmacokinetics*; D003198:Computer Simulation; D018592:Cross-Over Studies; D004347:Drug Interactions; D006801:Humans; D008297:Male; D008954:Models, Biological; D015742:Propofol / Q000493:pharmacokinetics*
D018686:Anesthetics, Intravenous; D015760:Alfentanil; D015742:Propofol