Summary
Changes in time course effected by cortisol suppression and the relationship of these changes to the plasma dexamethasone concentration of suppressor and non-suppressor patients are described in this report on a combined pharmacokinetic-pharmacodynamic model.
Thirteen depressed patients (8 suppressors and 5 non-suppressors) received an intravenous dose (1.5 mg) of dexamethasone. The drug-induced effect changes are found to lag behind, in time, the plasma drug level changes. To accurately relate the temporal relationship of effect changes to plasma dexamethasone levels, a pharmacodynamic model (sigmoid-Emax) was combined with a pharmacokinetic model that incorporated an effect compartment. The magnitude of the time-lag was quantified by the half-time of equilibration between concentrations in the hypothetical effect compartment and the plasma dexamethasone levels (t½keo).
The t½keo of the nonsuppressing group was about 50 of that of the suppressing group, indicating that for a given plasma level the onset and termination of effect for the nonsuppressing group is about two times more rapid than for the suppressing group. Moreover, the model can estimate the effect-site concentration that causes one-half of the maximal predicted effect (EC50), a measure of an individual's sensitivity to dexamethasone. The receptor sensitivity (as determined from the EC50 ratio) of the suppressing group was about twice that of the nonsuppressing group.
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References
Arana GW, Workman RJ, Baldessarini RJ (1984) Association between low plasma levels of dexamethasone and elevated levels of cortisol in psychiatric patients given dexamethasone. Am J Psychiatry 141: 1619–1620
Berger M, Pirke K-M, Doerr P, Krieg J-C, von Zerssen D (1984) The limited utility of dexamethasone suppression test for the diagnostic process in psychiatry. Br J Psychiatry 145: 372–383
Carroll BJ, Curtis GC, Mendels J (1976) Neuroendocrine regulation in depression I: limbic system adrenocortical dysfunction. Arch Gen Psychiatry 33: 1039–1044
Carroll BJ, Feinberg M, Greden JF, Haskett RF, McI James N, Steiner M, Tarika J (1980 A) Diagnosis of endogenous depression: comparison of clinical, research and neuroendocrine criteria. J Affect Dis 2: 177–194
Carroll BJ, Feinberg M, Greden JF, Tarika J, Albala AA, Haskett RF, McI James N, Kronfol Z, Lohr N, Steiner M, de Vigne JP, Young E (1981) A specific laboratory test for the diagnosis of melancholia. Arch Gen Psychiatry 38: 15–22
Carroll BJ, Schroeder K, Mukhopadhyay S, Greden JR, Feinberg M, Ritchie JC, Tarika J (1980 B) Plasma dexamethasone concentrations and cortisol suppression response in patients with endogenous depression. J Clin Endocrinol Metab 51: 433–437
Colburn WA (1981) Simultaneous pharmacokinetic and pharmacodynamic modeling. J Pharmacokin Biopharm 7: 159–179
Gibaldi M, Perrier D (1982) In: Swarbric J (ed) Pharmacokinetics. 2nd edn, Dekker, New York, pp 81–88
Grevel J, Brownell J, Steimer JL, Gaillard RC, Rosenthaler J (1986) Description of time course of the prolactin suppressant effect of the dopamine agonist CQP201-403 by an integrated pharmacokinetic-pharmacodynamic model. Br J Clin Pharmacol 22: 1–13
Gupta SK, Ellinwood EH, Nikaido AM, Heatherly DG (1990) Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of benzodiazepines: I. lorazepam. J Pharmacokin Biopharm 18: 89–102
Haack D, Gunther D, Kunkel G, Lichtwald K, Tanber U, Vecsei P (1981) Radioimmunological determination of synthetic glucocorticoids. Atemweg-Lungenkrankheiten 7: 283–289
Hofford NHG, Sheiner LB (1981) Undertanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokin 6: 429–453
Holsboer F (1983) Prediction of clinical course by dexamethasone suppression test (DST) response in depressed patients: physiological and clinical construct validity of the DST. Pharmacopsychiatria 15: 186–191
Johnson GF, Hunt G, Kerr K, Caterson I (1984) Dexamethasone suppression test (DST) and plasma dexamethasone levels in depressed patients. Psychiatry Res 13: 305–313
Metzler CM, Elfring GL, McEween AJ (1974) A package of computer programs for pharmacokinetic modeling. Biometrics 30: 562–563
Maguire KP, Tuckwell VM, Schweitzer I, Tiller JWG, Davis BM (1990) Dexamethasone kinetics in depressed patients before and after clinical response. Psychoneuroendocrinol 15: 113–123
Morris H, Carr V, Gilliand J, Hopper M (1986) Dexamethasone concentrations and the dexamethasone suppression tests in psychiatric disorders. Br J Psychiatry 148: 66–69
Rush AJ, Schlesser MA, Giles DE, Crowley GT, Fairchild C, Altshuler KZ (1982) The effect of dosage on the dexamethasone suppression test in normal controls. Psychiatry Res 7: 277–285
Sheiner LB, Stanski DR, Vozeh S, Miller RD, Ham J (1979) Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubercurarine. Clin Pharmacol Ther 25: 358–371
Yamaoka K, Nakagawa T, Uno T (1978) Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokin Biopharm 6: 165–175
Weidemann K, Holsboer F (1987) Plasma dexamethasone kinetics during the DST after oral and intravenous administration of the test drug. Biol Psychiatry 22: 1340–1348
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Gupta, S.K., Ritchie, J.C., Ellinwood, E.H. et al. Modeling the pharmacokinetics and pharmacodynamics of dexamethasone in depressed patients. Eur J Clin Pharmacol 43, 51–55 (1992). https://doi.org/10.1007/BF02280754
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DOI: https://doi.org/10.1007/BF02280754