Pharmacokinetic-pharmacodynamic modelling of fluvoxamine 5-HT transporter occupancy in rat frontal cortex.
OBJECTIVE
The pharmacokinetic-pharmacodynamic (PK-PD) correlation of fluvoxamine 5-HT transporter (SERT) occupancy was determined in rat frontal cortex ex vivo.


METHODS
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.


RESULTS
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 (P<0.01), presumably as a result of nonlinear brain distribution.


CONCLUSIONS
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.
Geldof
M
M
Department of Pharmacology, Leiden-Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
Freijer
J I
JI
van Beijsterveldt
L
L
Langlois
X
X
Danhof
M
M
D000465:Algorithms; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003627:Data Interpretation, Statistical; D016666:Fluvoxamine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007091:Image Processing, Computer-Assisted; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008297:Male; D017551:Microdialysis; D008954:Models, Biological; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*
D016666:Fluvoxamine; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors