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Pharmacokinetic/Pharmacodynamic Feedback Modelling of the Functional Corticosterone Response in Rats after Acute Treatment with Escitalopram
Author(s) -
Bundgaard Christoffer,
Larsen Frank,
Jørgensen Martin,
Mørk Arne
Publication year - 2007
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2006.00029.x
Subject(s) - escitalopram , corticosterone , pharmacodynamics , reuptake inhibitor , pharmacology , pharmacokinetics , serotonin , blood sampling , endocrinology , medicine , reuptake , chemistry , antidepressant , hippocampus , receptor , hormone
The objective of this study was to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of the drug‐induced corticosterone response after administration of escitalopram in rats. To achieve this, a mechanistic feedback turnover model mimicking the acute mechanism of action of selective serotonin reuptake inhibitors was assessed. Conscious and freely moving rats received constant rate infusions of 2.5, 5 or 10 mg/kg escitalopram or vehicle over 60 min. Automated serial blood sampling was conducted to determine escitalopram and corticosterone concentrations. The PK/PD model consisted of a turnover model of escitalopram‐evoked changes in response, which included an inhibitory feedback moderator function. Accordingly, response acted linearly on the production ( k tol ) of the moderator, which acted inversely on the production ( k in ) of response. The escitalopram plasma kinetics served as input to an inhibitory function acting on the loss ( k out ) of response. The corticosterone responses were successfully described using the model by fitting responses from all doses simultaneously resulting in estimation of drug parameters ( I max , IC 50 and n ) in addition to system parameters ( k in , k out and k tol ) for the whole exposure range. Thus, the applicability of the model for analysis of the acute selective serotonin reuptake inhibitor‐induced corticosterone response including acute auto‐inhibitory feedback was demonstrated.