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Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of benzodiazepines I: Lorazepam

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Abstract

This investigation compares the time course changes in the central nervous system (CNS) impairment effects on psychomotor and cognitive skills and relates these changes to the plasma lorazepam concentrations in a pharmacokinetic-pharmacodynamic (PK-PD) model. Six male subjects received a single oral dose of lorazepam or placebo. The CNS effects were measured by using computerized continuous tracking (TRKN), body sway with eyes open (SWAY OPEN), and digit symbol substitution (DSS) tests. Plasma lorazepam concentrations were best characterized by a two-compartment model with first-order absorption. Plotting the plasma lorazepam concentration and measured effect across time revealed a counterclockwise hysteresis loop. Fitting the time course of the effects in an integrated PK-PD model required an effect compartment with the equilibrium rate constant between it and the plasma compartment. The magnitude of the temporal lag was quantified by the half-time of equilibration between concentration in the hypothetical effect compartment and the plasma lorazepam level (t1/2keo).The CNS effect measured by TRKN was characterized by a mean estimate of maximum predicted effect (E max )of 418 with a t1/2keo of 0.43 hr, an estimate of effect site drug level to produce 50%of E max (EC50)of 35.8 ng/ml and a power parameter (γ) of 6.29.Corresponding parameter mean estimates for SWAY OPEN and DSS as measures of drug CNS effect were quite similar.

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References

  1. C. Bellantuono, N. Reggi, G. Tognoni, and S. Garattini. Benzodiazepines: Clinical pharmacology and therapeutic use.Drugs 19:195–219 (1980).

    Article  CAS  PubMed  Google Scholar 

  2. B. Ameer and D. J. Greenblatt. Lorazepam: A review of its clinical pharmacological properties and therapeutic uses.Drugs 21:161–200 (1981).

    Article  CAS  Google Scholar 

  3. D. D. Breimer, R. Jochemsen, and H. H. von Albert. Pharmacokinetics of benzodiazepines. Short-acting versus long-acting.Arzneim. Forsch. 30:875–881 (1980).

    CAS  Google Scholar 

  4. R. M. Arendt, D. J. Greenblatt, R. H. DeJong, J. D. Bonin, D. R. Abernethy, B. L. Ehrenberg, H. G. Giles, E. M. Sellers, and R. I. Shader. In vitro correlates of benzodiazepine cerebrospinal fluid uptake, pharmacodynamic action and peripheral distribution.J. Pharmacol Exp. Ther. 227:98–105 (1983).

    CAS  PubMed  Google Scholar 

  5. M. L. Jack, W. A. Colburn, N. M. Spirt, G. Bautz, M. Zanko, W. D. Horst, and R. A. O'Brien. A pharmacokinetic/pharmacodynamic/receptor binding model to predict the onset and duration of pharmacological activity of the benzodiazepines.Prog. Neuropsychopharmacol. Biol. Psychiat. 7:629–635 (1983).

    Article  CAS  Google Scholar 

  6. B. Dubnick, A. S. Lippa, C. A. Klepner, J. Coupet, E. M. Greenblatt, and B. Beer. The separation of3H-benzodiazepine sites in brain and of benzodiazepine pharmacology properties.Pharmacol. Biochem. Behav. 18:311–318 (1983).

    Article  CAS  PubMed  Google Scholar 

  7. M. B. Scharf and J. A. Jacoby. Lorazepam side effects and rebound phenomena.Clin. Pharmacol. Ther. 31:175–179 (1982).

    Article  CAS  PubMed  Google Scholar 

  8. D. J. Greenblatt, R. L. Shader, K. Franke, D. S. MacLaughlin, J. S. Harmatz, M. D. Allen, A. Wermer, and E. Woo. Pharmacokinetics and bioavailability of intravenous, intramuscular and oral iorazepam in humans.J. Pharm. Sci. 68:57–63 (1979).

    Article  CAS  PubMed  Google Scholar 

  9. J. D. Fenstermacher, R. G. Blasberg, and C. S. Patlak. Methods for quantifying the transport of drug across the brain barrier systems.Pharm. Ther. 14:217–248 (1981).

    Article  CAS  Google Scholar 

  10. J. Boon, M. Bourdouxhe, M. Breulet, M. Parent, and D. I. Bobon. Pilot clinical trial of parental Iorazepam (Temesta) in anxiety status.Psychopharmacology 33:377–384 (1973).

    Article  Google Scholar 

  11. H. W. Elliott. Metabolism of Iorazepam.Br. J. Anaesth. 48:1017–1023 (1976).

    Article  CAS  PubMed  Google Scholar 

  12. J. W. Dundee, W. A. W. McGown, J. K. Lilburh, A. C. McKay, and J. E. Hegerty. Comparison of the action of diazepam and lorazepam.Br. J. Anaesth. 51:439–445 (1979).

    Article  CAS  PubMed  Google Scholar 

  13. H. W. Elliott, N. Nomof, G. Navarro, H. W. Ruelius, J. A. Kuowles, and W. H. Comer. Central nervous system and cardiovascular effects of lorazepam in man.Clin. Pharmacol. Ther. 12:468–481 (1970).

    Google Scholar 

  14. T. Seppala, K. Korttila, S. Hakkinem, and M. Linnoila. Residual effects and skills related to driving after a single oral administration of diazepam, medazepam or lorazepam.Br. J. Clin. Pharmacol. 3:831–841 (1976).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. R. I. Shader, D. Dreyfuss, J. R. Gerrein, J. S. Harmatz, S. J. Allison, and D. J. Greenblatt. Sedative effects and impaired learning and recall after single oral dose of lorazepam.Clin. Pharmacol. Ther. 39:526–529 (1986).

    Article  CAS  PubMed  Google Scholar 

  16. S. E. File and A. J. Bond. Impaired performance and sedation after a single dose of lorazepam.Psychopharmacology 66:309313 (1979).

    Article  Google Scholar 

  17. H. V. Curran, W. Schiwy, and M. Lader. Differential amnesic properties of benzodiazepines: a dose-response comparison of two drugs with similar elimination half-lives.Psychopharmacology 92:358–364 (1987).

    Article  CAS  PubMed  Google Scholar 

  18. G. C. Preston, P. Broks, C. Ward, P. Poppleton, and S. M. Stahl. Effects of lorazepam on memory, attention and sedation in man.Psychopharmacology 95:208–215 (1988).

    Article  CAS  PubMed  Google Scholar 

  19. T. Roth, K. M. Hartse, P. G. Saab, P. M. Piccione, and M. Kramer. The effect of flurazepam, lorazepam and triazolam on sleep and memory.Psychopharmacology 70:231–237 (1980).

    Article  CAS  PubMed  Google Scholar 

  20. E. H. Ellinwood, M. Linnoila, H. V. Angel, J. W. Moore, J. T. Skinner, M. Easler, and D. W. Molter. Use of simple tasks to test impairment of complex skills by a sedative.Psychopharmacology 73:350–354 (1981).

    Article  CAS  PubMed  Google Scholar 

  21. E. H. Ellinwood, M. Linnoila, M. E. Easler, and D. W. Molter. Onset of peak impairment after diazepam and after alcohol.Clin. Pharmacol. Ther. 30:534–538 (1981).

    Article  CAS  PubMed  Google Scholar 

  22. M. M. Ghoneim, S. P. Mewaldt, and J. W. Hinrich. Dose-response analysis of the behavioral effects of diazepam: II. psychomotor performance, and mood.Psychopharmacology 82:296–300 (1984).

    Article  CAS  PubMed  Google Scholar 

  23. K. H. Mauritz, J. Dichgans, and A. Hufschmidt. Quantitative analysis of stance in late cortical cerebellar atrophy of the anterior lobe and other forms of cerebellar ataxia.Brain 102:461–482 (1979).

    Article  CAS  PubMed  Google Scholar 

  24. K. Korttila, M. M. Ghoneim, L. Jacobs, and R. S. Lakes. Evaluation of instrumental force platform as a test to measure residual effects of anesthetics.Anesthesiology 55:625–630 (1981).

    Article  CAS  PubMed  Google Scholar 

  25. D. Weschler.Weschler Adult Intelligence Scale-Revised Manual, Psychological Corp., Cleveland, OH, 1981.

    Google Scholar 

  26. D. J. Greenblatt, K. Franke, and R. I. Shader, Analysis of lorazepam and its glucuronide metabolite by electron-capture gas-liquid chromatography.J. Chromatog. 146:311–320 (1978).

    Article  CAS  Google Scholar 

  27. A. Dunne. JANA: A new iterative polyexponential curve stripping problem.Comput. Meth. Prog. Biomed. 20:269–275 (1985).

    Article  CAS  Google Scholar 

  28. C. M. Metzler, G. L. Elfring, and A. J. McEwen. A package of computer programs for pharmacokinetic modeling.Biometrics 30:562–563 (1974).

    Article  Google Scholar 

  29. M. Gibaldi and D. Perrier. In J. Swarbrick (ed.),Pharmacokinetics, 2nd ed., Marcel Dekker, New York, 1982, pp. 81–88.

    Google Scholar 

  30. D. Perrier and M. Mayersohn. Non-compartmental determination of the steady-state volume of distribution for any mode of administration.J. Pharm. Sci. 71:372–373 (1982).

    Article  CAS  PubMed  Google Scholar 

  31. L. B. Sheiner, D. R. Stanski, S. Vozeh, R. D. Miller, and J. Ham. Simultaneous modeling of pharmacokinetics and pharmacodynamics: Application to d-tubocurarine.Clin. Pharmacol. Ther. 25:358–371 (1979).

    CAS  PubMed  Google Scholar 

  32. N. H. G. Holford and L. B. Sheiner. Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models.Clin. Pharmacokin. 6:429–453 (1981).

    Article  CAS  Google Scholar 

  33. SAS.SAS User's Guide;Statistics, Version 5, SAS Institute, Cary, NC, 1985.

  34. D. J. Greenblatt, M. D. Allen, D. S. MacLaughlin, D. H. Huffman, J. S. Harmatz, and R. I. Shader. Singleand multiple-dose kinetics of oral lorazepam in humans: The predictability of accumulation.J. Pharmacokin. Biopharm. 7:159–179 (1979).

    Article  CAS  Google Scholar 

  35. W. A. Colburn. Simultaneous pharmacokinetic and pharmacodynamic modeling.J. Pharmacokin. Biopharm. 9: 367–388 (1981).

    Article  CAS  Google Scholar 

  36. L. Aaltonen, J. Kanto, and M. Salo. Cerebrospinal fluid concentrations and serum protein binding of lorazepam and conjugate.Acta Pharmacol. Toxicol. 46:156–157 (1980).

    Article  CAS  Google Scholar 

  37. S. A. Kaplan and M. L. Jack. Metabolism of the benzodiazepines: pharmacokinetic and pharmacodynamic consideration. In E. Costa (ed.),The Benzodiazepine: From Molecular Biology to Clinical Practice, Raven Press, New York, 1983, pp. 173–199.

    Google Scholar 

  38. R. C. Speth, G. J. Wastek, P. C. Johnson, and H. I. Yamamura. Benzodiazepine binding in human brain: characterization using [3H]flunitrazepam.Life Sci. 22:859–866 (1978).

    Article  CAS  PubMed  Google Scholar 

  39. S. E. File and R. G. Lister. Does tolerance to lorazepam develop with once weekly dosing?Br. J. Clin. Pharmacol. 16:645–650 (1983).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. M. Sunzel, L. Paalzow, L. Berggren, and I. Griksson. Respiratory and cardiovascular effects in relation to plasma levels of midazolam and diazepam.Br. J. Clin. Pharmacol. 25:561–569 (1988).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. F. C. Lam, C. T. Hung, and D. G. Perrier. Estimation of variance for harmonic mean half-lives.J. Pharm. Sci. 74:229–231 (1985).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Psychiatry, Duke University Medical Center, Box 3870, 27710, Durham, North Carolina

    Samir K. Gupta, Everett H. Ellinwood, Arlene M. Nikaido & Douglas G. Heatherly

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  1. Samir K. Gupta
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  2. Everett H. Ellinwood
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  3. Arlene M. Nikaido
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  4. Douglas G. Heatherly
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This research was supported by a grant from the National Institute on Drug Abuse, #DA-01883.

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Gupta, S.K., Ellinwood, E.H., Nikaido, A.M. et al. Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of benzodiazepines I: Lorazepam. Journal of Pharmacokinetics and Biopharmaceutics 18, 89–102 (1990). https://doi.org/10.1007/BF01063553

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