Modeling of the effect site equilibration kinetics and pharmacodynamics of racemic baclofen and its enantiomers using quantitative EEG effect measures

JW Mandema, CD Heijligers-Feijen, E Tukker, AG De Boer and M Danhof

Center for Bio-Pharmaceutical Sciences, Sylvius Laboratory, University of Leiden, The Netherlands.

The plasma to effect site equilibration kinetics and the steady-state plasma concentration-EEG effect relationship of baclofen were characterized after separate administration of racemic baclofen and its two enantiomers. Male Wistar-derived rats received an i.v. infusion of 1.25 mg of racemic, 0.63 mg of R- or 1.25 mg of S-baclofen in 10 min. Frequent arterial blood samples were obtained and the EEG was continuously quantified using aperiodic analysis. The baclofen-induced decrease in amplitudes in the 11.5 to 30 Hz frequency band was used as an EEG effect measure. The delay between plasma concentrations and EEG effect measure was best modeled by a monoexponential conductance function. No differences were observed with respect to the rate of equilibration between plasma and effect for racemic, R- and S-baclofen, with values of the time to reach 50% equilibrium (BET50ss) of (mean +/- S.E.) 23 +/- 4 min, 35 +/- 6 min and 32 +/- 7 min, respectively. The steady-state plasma concentration-EEG effect relationships of racemic and R-baclofen were characterized by the sigmoidal Emax model. The EEG effects of the S-isomer were small and best described by a linear pharmacodynamic model. The pharmacodynamic parameters of the R-isomer were: Emax = -20 +/- 2 microV/sec, EC50 = 0.61 +/- 0.11 mg/l and N = 3.7 +/- 0.7, and not significantly different from the parameters of the racemate when only the "active" R-isomer was taken into account. This indicates that no pharmacodynamic interactions between the two enantiomers occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 261, Issue 1, pp. 88-95, 04/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics