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Estimating the rate of thiopental blood-brain equilibration using pseudo steady state serum concentrations

  • Pierre O. Maitre
  • Michael Bührer
  • Steven L. Shafer
  • Donald R. Stanski
Article

Abstract

The equilibration between drug serum concentration and drug effect under non-steady state concentrations has been classically modeled using an effect compartment where the transfer from the serum to the effect compartment is considered to be a first-order process. The purpose of the present study was to examine whether an effect compartment with first-order transfer was adequate for describing thiopental serum concentration-EEG pharmacodynamics. The study has two facets: (i) Successive pseudo steady state serum concentrations of thiopental having a square wave shape were produced and maintained in six human subjects by means of a computer-driven infusion pump. An aperiodic wave form transformation of the electroencephalogram (EEG) was used as a continuous measure of thiopental EEG drug effect. The time course of the EEG effect following each thiopental serum concentration square wave showed an exponential pattern. The first-order rate constant for equilibration of the effect site concentration with the drug serum concentration (k eo ) was estimated by fitting a monoexponential model to the effect vs. time data resulting from the pseudo steady state thiopental serum concentration profile, (ii) In a second experiment, data were obtained from a classical design, i.e., a zero-order intravenous infusion of thiopental. The same subjects were studied. The k eo was estimated by means of a semipammetric iterative method using convolution (effect compartment, transfer of drug from serum to site of action is assumed to be a first-order process). The mean pseudo steady state value for k eo of 0.51 min−1was not different from the mean value of 0.46 min−1from the semi parametric approach when data from a linear portion of the drug concentration vs. effect curve were examined. The pseudo steady state technique gave inaccurate estimates of k eo in the nonlinear portion of the thiopental concentration vs. response curve, i.e., at the peak of the biphasic concentration-effect relationship.

Key words

pharmacodynamic modeling pharmacokinetic modeling thiopental effect compartment pseudo steady state computer-driven infusion scheme 

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Copyright information

© Plenum Publishing Corporation 1990

Authors and Affiliations

  • Pierre O. Maitre
    • 1
    • 2
    • 3
  • Michael Bührer
    • 1
    • 2
    • 3
  • Steven L. Shafer
    • 1
    • 3
  • Donald R. Stanski
    • 1
    • 3
  1. 1.Department of AnesthesiologyStanford UniversityStanford
  2. 2.Department of Anesthesiology and Intensive CareUniversity of Bern, InselspitalBernSwitzerland
  3. 3.Anesthesiology Service (112A)Veterans Administration Medical CenterPalo Alto

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