Pharmacokinetic–pharmacodynamic modelling of fluvoxamine 5-HT transporter occupancy in rat frontal cortex
| Autor: | Geldof, M, Freijer, J I, van Beijsterveldt, L, Langlois, X, Danhof, M |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Male
Serotonin Plasma Membrane Transport Proteins Microdialysis Prefrontal Cortex In Vitro Techniques Research Papers Models Biological Rats Fluvoxamine Data Interpretation Statistical Image Processing Computer-Assisted Animals Rats Wistar Infusions Intravenous Algorithms Chromatography High Pressure Liquid Selective Serotonin Reuptake Inhibitors |
| Popis: | The pharmacokinetic-pharmacodynamic (PK-PD) correlation of fluvoxamine 5-HT transporter (SERT) occupancy was determined in rat frontal cortex ex vivo.Rats (n=47) with permanent arterial and venous cannulas received a 30 min intravenous infusion of fluvoxamine (1 or 7.3 mg kg(-1)). At various time points after dosing, brains were collected for determination of fluvoxamine concentration and SERT occupancy. In addition, the time course of fluvoxamine concentration in plasma was determined up to the time of brain collection. In a separate study (n=26), the time course of fluvoxamine concentration in brain extracellular fluid (ECF) and plasma was determined. The results of the investigations were interpreted by nonlinear mixed effects modeling.Highest SERT occupancy was reached at the first time point (10 or 15 min) and maintained for 1.5 and 7 h after 1 and 7.3 mg kg(-1), respectively. Thereafter, SERT occupancy decreased linearly at a rate of 8% h(-1). SERT occupancy could be directly related to plasma, brain ECF and brain tissue concentrations by a hyperbolic function (Bmax model). Maximal SERT occupancy (Bmax) was 95%. Estimated concentrations at half-maximal SERT occupancy (EC50) in plasma, ECF and brain tissue were 0.48, 0.22 and 14.8 ng mL(-1) respectively. The minimum value of the objective function decreased 12 points for ECF and brain tissue concentrations relative to plasma (P0.01), presumably as a result of nonlinear brain distribution.The proposed PK-PD model constitutes a useful basis for prediction of the time course of ex vivo SERT occupancy in behavioural studies with selective serotonin reuptake inhibitors. |
| Databáze: | OpenAIRE |
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