Pharmacokinetic modeling of non-linear brain distribution of fluvoxamine in the rat.
BACKGROUND
A pharmacokinetic (PK) model is proposed for estimation of total and free brain concentrations of fluvoxamine.


METHODS
Rats with arterial and venous cannulas and a microdialysis probe in the frontal cortex received intravenous infusions of 1, 3.7 or 7.3 mg.kg(-1) of fluvoxamine.


METHODS
With increasing dose a disproportional increase in brain concentrations was observed. The kinetics of brain distribution was estimated by simultaneous analysis of plasma, free brain ECF and total brain tissue concentrations. The PK model consists of three compartments for fluvoxamine concentrations in plasma in combination with a catenary two compartment model for distribution into the brain. In this catenary model, the mass exchange between a shallow perfusion-limited and a deep brain compartment is described by a passive diffusion term and a saturable active efflux term.


RESULTS
The model resulted in precise estimates of the parameters describing passive influx into (k in) of 0.16 min(-1) and efflux from the shallow brain compartment (k out) of 0.019 min(-1) and the fluvoxamine concentration at which 50% of the maximum active efflux (C 50) is reached of 710 ng.ml(-1). The proposed brain distribution model constitutes a basis for precise characterization of the PK-PD correlation of fluvoxamine by taking into account the non-linearity in brain distribution.
Geldof
Marian
M
Division of Pharmacology, Leiden-Amsterdam Center for Drug Research, Leiden University, PO Box 9502, 2300 RA, Leiden, The Netherlands.
Freijer
Jan
J
van Beijsterveldt
Ludy
L
Danhof
Meindert
M
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002199:Capillary Permeability; D016666:Fluvoxamine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008297:Male; D017551:Microdialysis; D008954:Models, Biological; D017711:Nonlinear Dynamics; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D018687:Antidepressive Agents, Second-Generation; D016666:Fluvoxamine; D017367:Selective Serotonin Reuptake Inhibitors
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