Abstract
The objective of this study was the construction of a pharmacokinetic-pharmacodynamic model to describe the effects of chlorprothixene on prolactin secretion and the time-dependent alterations in the concentration-effect relationship due to tolerance development. Prolactin and chlorprothixene serum concentrations were determined in eight healthy men for up to 72 h after the intravenous and oral administration of chlorprothixene. An integrated pharmacokinetic model and a physiological indirect pharmacodynamic/tolerance model were applied to describe the prolactin-secreting effect of chlorprothixene. A three-compartment model served as pharmacokinetic model. The pharmacodynamic and tolerance model accounted for the baseline effect, the effect induced by the drug, and the regulatory mechanism that opposes the effect of the drug. This model adequately characterized the prolactin response after intravenous and oral drug administration of each individual by the sensitivity (dissociation constant), the efficacy (maximal prolactin secretion rate), the extent, and the rate of tolerance development. We speculate that this approach improves the quality of neuroendocrine challenge tests to determine the subject’s sensitivity to drugs and the time course of adaptation.
Footnotes
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Send reprint requests to: Dr. Metin Bagli, Klinik und Poliklinik für Psychiatrie und Psychotherapie, Rheinische Friedrich-Wilhelms-Universität, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany. E-mail: bagli{at}uni-bonn.de
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↵FN1 Present address: Department of General Psychiatry, University of Vienna, Austria.
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↵FN2 Present address: Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany.
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Received for publication December 15, 1998.
- Abbreviations:
- rin.prl
- prolactin secretion rate
- rin.prl.max
- maximal prolactin secretion rate
- rin.prl.p
- prolactin secretion rate without compensatory increase of T
- rin.prl.0
- baseline secretion rate of prolactin
- rin.prl.50
- prolactin secretion rate obtained by 50% inhibition of the prolactin-lowering effects of T
- rin.T
- secretion rate of T
- rin.T.0
- baseline secretion rate of T
- ccpx
- chlorprothixene concentration
- cda
- dopamine concentration
- cprl
- prolactin concentration
- cprl.p
- prolactin concentration that results from rin.prl.p
- css.prl.0
- cprl at baseline
- EC50
- dopamine concentration producing 50% rin.prl.max
- ET
- extent of tolerance
- IC50
- chlorprothixene concentration required to produce rin.prl.50
- IC50.p
- IC50without compensatory increase of T
- IC50.n
- IC50 with compensatory increase of T
- kel.prl
- prolactin elimination rate constant
- KI
- chlorprothixene dissociation constant at the dopamine D2 receptor
- ktol
- rate of tolerance development
- mprl
- mass of prolactin
- P
- proportionality factor
- T
- EC50-normalized dopamine concentration
- Tss.IC50n
- T at steady state forccpx = IC50.n
- Tss.IC50p
- T at steady state forccpx = IC50.p
- Tss.0
- T at baseline
- Vprl
- volume of distribution of prolactin
- Accepted July 15, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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Pharmacokinetic-Pharmacodynamic Modeling of Tolerance to the Prolactin-Secreting Effect of Chlorprothixene after Different Modes of Drug Administration
