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Influence of different fat emulsion-based intravenous formulations on the pharmacokinetics and pharmacodynamics of
E H Cox1, C A Knibbe, V S Koster
1Division of Pharmacology, University of Leiden, Sylvius Laboratory, The Netherlands.
Purpose:
The influence of different intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol was investigated using the effect on the EEG (11.5-30 Hz) as pharmacodynamic endpoint.
Methods:
Propofol was administered as an intravenous bolus infusion (30 mg/kg in 5 min) or as a continuous infusion (150 mg/kg in 5 hours) in chronically instrumented male rats. Propofol was formulated as a 1% emulsion in an Intralipid 10%-like fat emulsion (Diprivan-10, D) or as a 1%- or 6% emulsion in Lipofundin MCT/LCT-10% (P1% and P6%, respectively). EEG was recorded continuously and arterial blood samples were collected serially for the determination of propofol concentrations using HPLC.
Results:
Following bolus infusion, the pharmacokinetics of the various propofol emulsions could adequately be described by a two-compartmental pharmacokinetic model. The average values for clearance (Cl), volume of distribution at steady-state (Vd,ss) and terminal half-life (t1/2, lambda 2) were 107 +/- 4 ml/min/kg, 1.38 +/- 0.06 l/kg and 16 +/- 1 min, respectively (mean +/- S.E. n = 22). No significant differences were observed between the three propofol formulations. After continuous infusion these values were 112 +/- 11 ml/min/kg, 5.19 +/- 0.41 l/kg and 45 +/- 3 min, respectively (mean +/- S.E., n = 20) with again no statistically significant differences between the three propofol formulations. Comparison between the bolus- and the continuous infusion revealed a statistically significant difference for both Vd,ss and t1/2, lambda 2 (p < 0.05), whereas Cl remained unchanged. In all treatment groups infusion of propofol resulted in a burst-suppression type of EEG. A profound hysteresis loop was observed between blood concentrations and EEG effect for all formulations. The hysteresis was minimized by a semi-parametric method and resulted in a biphasic concentration-effect relationship of propofol that was described non-parametrically. For P6% a larger rate constant onset of drug effect (t1/2,keo) was observed compared to the other propofol formulations (p < 0.05).
Conclusions:
The pharmacokinetics and pharmacodynamics of propofol are not affected by to a large extent the type of emulsion nor by the concentration of propofol in the intravenous formulation.