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Abstract nr. P6 Ph.d.-studerende Christoffer Bundgaard Institut for Farmakologi Studiestart 1. juli 2001 Vejledere Bjarne Fjalland, Martin Jørgensen 1, Frank Larsen 2, Arne Mørk 3 Titel på forskningsprojekt Quantitative pharmacokinetic/pharmacodynamic (PK/PD) relationships and modelling approaches of selective serotonin reuptake inhibitors (SSRIs) 1 Early Development Pharmacokinetics, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby H. Lundbeck A/S, Ottiliavej 9, 2500 Valby 3 Neurochemistry & Discovery ADME, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby 2 Pharmacokinetics/-Dynamics, Simultaneous microdialysis-blood sampling approach for characterization of PK/PD relationships of antidepressant drugs in rats The present study describes an animal model suitable for pharmacokinetic/pharmacodynamic (PK/PD) investigations of antidepressant drugs. The model demonstrates the utility of an intracerebral microdialysis system coupled with an automated blood sampling device designed for conscious, freely moving rats. The simultaneous microdialysis-blood sampling approach provides the opportunity to study, in the same animal and at the same time, the following PK/PD parameters: 1) 2) 3) 4) Plasma concentrations of the drug under investigation and its metabolites Brain extracellular concentrations of the parent compound and its metabolites Changes in brain extracellular levels of endogenous substances (neurotransmitters) Changes in plasma levels of endogenous compounds (hormones). This rat model has been established to study the PK/PD of citalopram, a selective serotonin reuptake inhibitor (SSRI) used in the treatment of depressive disorder. Citalopram was administered intravenously as a bolus dose of 5 mg/kg and arterial blood samples were withdrawn at regular time intervals for determination of plasma concentrations citalopram. In addition, corticosterone, a steroid hormone released in the blood by activation of the hypothalamic-pituitary-adrenal (HPA) axis due to the citalopram treatment, was also measured in plasma as a PD marker. Microdialysis sampling was carried out in the ventral hippocampus of the brain for measurement of citalopram concentrations or baseline changes in serotonin (5HT) levels. All PK measurements carried out using microdialysis were corrected for incomplete recovery through the microdialysis membrane in order to determine true concentrations in the brain extracellular fluid. Using the described approach it was possible, in a single rat, to correlate the time-course of citalopram in plasma with the time-course in extracellular fluid in brain. Further, correlation of citalopram concentrations with the PD markers corticosterone and 5-HT is possible. The technique requires use of appropriate sensitive and specific analytical methods due to the trace amounts of especially neurotransmitters present in microdialysates.