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. 1992 Jan;105(1):164–170. doi: 10.1111/j.1476-5381.1992.tb14229.x

Differences in intrinsic efficacy of benzodiazepines are reflected in their concentration-EEG effect relationship.

J W Mandema 1, M T Kuck 1, M Danhof 1
PMCID: PMC1908634  PMID: 1350744

Abstract

1. The relevance of EEG effect parameters as a measure of the central nervous system effects of benzodiazepines was evaluated. The concentration-EEG effect relationships of the benzodiazepine agonist midazolam, partial agonist bretazenil, antagonist flumazenil and inverse agonist Ro 19-4603 were quantified and compared with the intrinsic efficacy and affinity of these compounds at the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex. 2. The pharmacokinetics and pharmacodynamics of the compounds were determined after a single intravenous bolus administration of 5 mg kg-1 midazolam, 2.5 mg kg-1 bretazenil, 10 mg kg-1 flumazenil or 2.5 mg kg-1 Ro 19-4603 to male Wistar derived rats. In a separate experiment the distribution between blood, cerebrospinal fluid and brain concentrations of these compounds was determined. A sensitive assay was developed to measure bretazenil and Ro 19-4603 concentrations in small samples of biological fluids. 3. The benzodiazepine-induced changes in amplitudes in the 11.5-30 Hz frequency band, as determined by aperiodic analysis, was used as EEG effect measure. Concentration-EEG effect relationships were derived by a pharmacokinetic-pharmacodynamic modelling procedure and in the case of midazolam, bretazenil and Ro 19-4603 successfully quantified by the sigmoidal Emax model. Large differences in maximal effect of midazolam (Emax = 73 +/- 2 microVs-1), bretazenil (Emax = 19 +/- 1 microVs-1) and Ro 19-4603 (Emax = -6.5 +/- 0.4 microVs-1) were observed, reflecting their differences in intrinsic efficacy. A close correlation was found between the EC50 values based on free drug concentration and receptor affinity as determined by displacement of [3H]-flumazenil in a washed brain homogenate at 37 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Arendt R. M., Greenblatt D. J., deJong R. H., Bonin J. D., Abernethy D. R., Ehrenberg B. L., Giles H. G., Sellers E. M., Shader R. I. In vitro correlates of benzodiazepine cerebrospinal fluid uptake, pharmacodynamic action and peripheral distribution. J Pharmacol Exp Ther. 1983 Oct;227(1):98–106. [PubMed] [Google Scholar]
  2. Belzung C., Misslin R., Vogel E. Anxiogenic effects of a benzodiazepine receptor partial inverse agonist, RO 19-4603, in a light/dark choice situation. Pharmacol Biochem Behav. 1990 Jul;36(3):593–596. doi: 10.1016/0091-3057(90)90260-o. [DOI] [PubMed] [Google Scholar]
  3. Bonetti E. P., Pieri L., Cumin R., Schaffner R., Pieri M., Gamzu E. R., Müller R. K., Haefely W. Benzodiazepine antagonist Ro 15-1788: neurological and behavioral effects. Psychopharmacology (Berl) 1982;78(1):8–18. doi: 10.1007/BF00470579. [DOI] [PubMed] [Google Scholar]
  4. Breimer L. T., Hennis P. J., Burm A. G., Danhof M., Bovill J. G., Spierdijk J., Vletter A. A. Quantification of the EEG effect of midazolam by aperiodic analysis in volunteers. Pharmacokinetic/pharmacodynamic modelling. Clin Pharmacokinet. 1990 Mar;18(3):245–253. doi: 10.2165/00003088-199018030-00006. [DOI] [PubMed] [Google Scholar]
  5. Brogden R. N., Goa K. L. Flumazenil. A preliminary review of its benzodiazepine antagonist properties, intrinsic activity and therapeutic use. Drugs. 1988 Apr;35(4):448–467. doi: 10.2165/00003495-198835040-00004. [DOI] [PubMed] [Google Scholar]
  6. Dingemanse J., Danhof M., Breimer D. D. Pharmacokinetic-pharmacodynamic modeling of CNS drug effects: an overview. Pharmacol Ther. 1988;38(1):1–52. doi: 10.1016/0163-7258(88)90101-5. [DOI] [PubMed] [Google Scholar]
  7. Dingemanse J., Sollie F. A., Breimer D. D., Danhof M. Pharmacokinetic modeling of the anticonvulsant response of oxazepam in rats using the pentylenetetrazol threshold concentration as pharmacodynamic measure. J Pharmacokinet Biopharm. 1988 Apr;16(2):203–228. doi: 10.1007/BF01062261. [DOI] [PubMed] [Google Scholar]
  8. File S. E., Pellow S. Intrinsic actions of the benzodiazepine receptor antagonist Ro 15-1788. Psychopharmacology (Berl) 1986;88(1):1–11. doi: 10.1007/BF00310505. [DOI] [PubMed] [Google Scholar]
  9. Gardner C. R. Functional in vivo correlates of the benzodiazepine agonist-inverse agonist continuum. Prog Neurobiol. 1988;31(6):425–476. doi: 10.1016/0301-0082(88)90011-1. [DOI] [PubMed] [Google Scholar]
  10. Greenblatt D. J., Ehrenberg B. L., Gunderman J., Locniskar A., Scavone J. M., Harmatz J. S., Shader R. I. Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam, and placebo. Clin Pharmacol Ther. 1989 Apr;45(4):356–365. doi: 10.1038/clpt.1989.41. [DOI] [PubMed] [Google Scholar]
  11. Gregory T. K., Pettus D. C. An electroencephalographic processing algorithm specifically intended for analysis of cerebral electrical activity. J Clin Monit. 1986 Jul;2(3):190–197. doi: 10.1007/BF01620551. [DOI] [PubMed] [Google Scholar]
  12. Haefely W. E. Pharmacology of the benzodiazepine receptor. Eur Arch Psychiatry Neurol Sci. 1989;238(5-6):294–301. doi: 10.1007/BF00449811. [DOI] [PubMed] [Google Scholar]
  13. Haefely W., Martin J. R., Schoch P. Novel anxiolytics that act as partial agonists at benzodiazepine receptors. Trends Pharmacol Sci. 1990 Nov;11(11):452–456. doi: 10.1016/0165-6147(90)90126-s. [DOI] [PubMed] [Google Scholar]
  14. Haefely W. Partial agonists of the benzodiazepine receptor: from animal data to results in patients. Adv Biochem Psychopharmacol. 1988;45:275–292. [PubMed] [Google Scholar]
  15. Holford N. H., Sheiner L. B. Kinetics of pharmacologic response. Pharmacol Ther. 1982;16(2):143–166. doi: 10.1016/0163-7258(82)90051-1. [DOI] [PubMed] [Google Scholar]
  16. Hollander-Jansen M., Dingemanse J., Langemeijer M. W., Danhof M. Relationship between receptor occupancy at 37 degrees C and the anticonvulsant effect of flunitrazepam in rats. Pharm Res. 1989 Jul;6(7):585–591. doi: 10.1023/a:1015901414495. [DOI] [PubMed] [Google Scholar]
  17. Hunkeler W., Möhler H., Pieri L., Polc P., Bonetti E. P., Cumin R., Schaffner R., Haefely W. Selective antagonists of benzodiazepines. Nature. 1981 Apr 9;290(5806):514–516. doi: 10.1038/290514a0. [DOI] [PubMed] [Google Scholar]
  18. Koopmans R., Dingemanse J., Danhof M., Horsten G. P., van Boxtel C. J. Pharmacokinetic-pharmacodynamic modeling of midazolam effects on the human central nervous system. Clin Pharmacol Ther. 1988 Jul;44(1):14–22. doi: 10.1038/clpt.1988.106. [DOI] [PubMed] [Google Scholar]
  19. Mandema J. W., Danhof M. Pharmacokinetic-pharmacodynamic modeling of the central nervous system effects of heptabarbital using aperiodic EEG analysis. J Pharmacokinet Biopharm. 1990 Oct;18(5):459–481. doi: 10.1007/BF01061705. [DOI] [PubMed] [Google Scholar]
  20. Mandema J. W., Gubbens-Stibbe J. M., Danhof M. Stability and pharmacokinetics of flumazenil in the rat. Psychopharmacology (Berl) 1991;103(3):384–387. doi: 10.1007/BF02244294. [DOI] [PubMed] [Google Scholar]
  21. Mandema J. W., Sansom L. N., Dios-Vièitez M. C., Hollander-Jansen M., Danhof M. Pharmacokinetic-pharmacodynamic modeling of the electroencephalographic effects of benzodiazepines. Correlation with receptor binding and anticonvulsant activity. J Pharmacol Exp Ther. 1991 Apr;257(1):472–478. [PubMed] [Google Scholar]
  22. Mandema J. W., Tukker E., Danhof M. Pharmacokinetic-pharmacodynamic modelling of the EEG effects of midazolam in individual rats: influence of rate and route of administration. Br J Pharmacol. 1991 Mar;102(3):663–668. doi: 10.1111/j.1476-5381.1991.tb12230.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Martin J. R., Pieri L., Bonetti E. P., Schaffner R., Burkard W. P., Cumin R., Haefely W. E. Ro 16-6028: a novel anxiolytic acting as a partial agonist at the benzodiazepine receptor. Pharmacopsychiatry. 1988 Nov;21(6):360–362. doi: 10.1055/s-2007-1021947. [DOI] [PubMed] [Google Scholar]
  24. Morgan P. F., Lloyd H. G., Stone T. W. Inhibition of adenosine accumulation by a CNS benzodiazepine antagonist (Ro 15-1788) and a peripheral benzodiazepine receptor ligand (Ro 05-4864). Neurosci Lett. 1983 Oct 31;41(1-2):183–188. doi: 10.1016/0304-3940(83)90244-6. [DOI] [PubMed] [Google Scholar]
  25. Moschitto L. J., Greenblatt D. J. Concentration-independent plasma protein binding of benzodiazepines. J Pharm Pharmacol. 1983 Mar;35(3):179–180. doi: 10.1111/j.2042-7158.1983.tb04302.x. [DOI] [PubMed] [Google Scholar]
  26. Möhler H., Okada T. The benzodiazepine receptor in normal and pathological human brain. Br J Psychiatry. 1978 Sep;133:261–268. doi: 10.1192/bjp.133.3.261. [DOI] [PubMed] [Google Scholar]
  27. Ongini E., Barzaghi C., Marzanatti M. Intrinsic and antagonistic effects of beta-carboline FG 7142 on behavioral and EEG actions of benzodiazepines and pentobarbital in cats. Eur J Pharmacol. 1983 Nov 11;95(1-2):125–129. doi: 10.1016/0014-2999(83)90276-5. [DOI] [PubMed] [Google Scholar]
  28. Pieri L., Schaffner R., Scherschlicht R., Polc P., Sepinwall J., Davidson A., Möhler H., Cumin R., Da Prada M., Burkard W. P. Pharmacology of midazolam. Arzneimittelforschung. 1981;31(12A):2180–2201. [PubMed] [Google Scholar]
  29. Polc P., Laurent J. P., Scherschlicht R., Haefely W. Electrophysiological studies on the specific benzodiazepine antagonist Ro 15-1788. Naunyn Schmiedebergs Arch Pharmacol. 1981 Jul;316(4):317–325. doi: 10.1007/BF00501364. [DOI] [PubMed] [Google Scholar]
  30. Potier M. C., Prado de Carvalho L., Venault P., Chapouthier G., Rossier J. Demonstration of the partial agonist profiles of Ro 16-6028 and Ro 17-1812 in mice in vivo. Eur J Pharmacol. 1988 Oct 26;156(1):169–172. doi: 10.1016/0014-2999(88)90161-6. [DOI] [PubMed] [Google Scholar]
  31. Yakushiji T., Fukuda T., Oyama Y., Akaike N. Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones. Br J Pharmacol. 1989 Nov;98(3):735–740. doi: 10.1111/j.1476-5381.1989.tb14600.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Yamaoka K., Nakagawa T., Uno T. Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm. 1978 Apr;6(2):165–175. doi: 10.1007/BF01117450. [DOI] [PubMed] [Google Scholar]

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