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Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man

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Abstract

The pharmacodynamics of a racemic mixture of ketamine R,S (±)-ketamine and of each enantiomer, S(+)-ketamine and R(−)-ketamine, were studied in five volunteers. The median frequency of the electroencephalogram (EEG) power spectrum, a continuous noninvasive measure of the degree of central nervous system (CNS) depression (pharmacodynamics), was related to measured serum concentrations of drug (pharmacokinetics). The concentration-effect relationship was described by an inhibitory sigmoid Emax pharmacodynamic model, yielding estimates of both maximal effect (Emax) and sensitivity (IC50) to the racemic and enantiomeric forms of ketamine. R(−)-ketamine was not as effective as R,S(±)-ketamine or S(+)-ketamine in causing EEG slowing. The maximal decrease (mean±SD) of the median frequency (Emax)for R(−)-ketamine was 4.4±0.5 Hz and was significantly different fromR,S (±)-ketamine (7.6 ±1.7 Hz) and S(+)-ketamine (8.3±1.9Hz). The ketamine serum concentration that caused one-half of the maximal median frequency decrease (IC50) was 1.8±0.5Μg/mL for R(−)-ketamine; 2.0±0.5 Μg/mL for R,S(±)-ketamine; and 0.8±0.4 Μg/mL for S(+)-ketamine. Because the maximal effect (Emax) of the R(−)-ketamine was different from that of S(+)-ketamine and R,S(±)-ketamine, it was not possible to directly compare the potency (i.e., IC50) of these compounds. Accordingly, a classical agonist/partial-agonist interaction model was examined, using the separate enantiomer results to predict racemate results. Although the model did not predict racemate results well, its failure was not so great as to provide clear evidence of synergism (or excess antagonism) of the enantiomers.

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Authors and Affiliations

  1. Anesthesiology Service (112A), Veterans Adminstration Medical Center, 94304, Palo Alto, California

    Jürgen Schüttler & Donald R. Stanski

  2. Department of Anesthesia, Stanford University School of Medicine, 94305, Stanford, California

    Jürgen Schüttler, Donald R. Stanski & Paul F. White

  3. Department of Pharmacology, University of California, 94143, San Francisco, San Francisco, California

    Anthony J. Trevor & Yukio Horai

  4. Department of Laboratory Medicine and Division of Clinical Pharmacology, School of Medicine, University of San Francisco, 94143, San Francisco, California

    Davide Verotta & Lewis B. Sheiner

Authors
  1. Jürgen Schüttler
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  2. Donald R. Stanski
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  3. Paul F. White
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  4. Anthony J. Trevor
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  5. Yukio Horai
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  6. Davide Verotta
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  7. Lewis B. Sheiner
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Additional information

This work was supported in part by a Starter Grant from the American Society of Anesthesiologists, the Biomedical Research Support Grant NIH 2S07RR5353-20, 1981, (P.F.W.); and NIH and NIA Research Grants NS-17956 and AG03104 (D.R.S., A.J.T., L.B.S). The research fellowship of Dr. Schüttler was made possible by a NATO Foundation Grant (300-402-511-3), awarded by the German Academic Exchange Service. This study is part of Dr. Schüttler's “Habilitation Thesis” for the Faculty of Medicine at the University of Bonn, West Germany. Dr. Verotta is a fellow of the program of advanced training established by EEC and Regione Lombardia on leave of absence from Mario Negri Institute of Pharmacological Research, Milan, Italy.

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Schüttler, J., Stanski, D.R., White, P.F. et al. Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man. Journal of Pharmacokinetics and Biopharmaceutics 15, 241–253 (1987). https://doi.org/10.1007/BF01066320

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  • DOI: https://doi.org/10.1007/BF01066320

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