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Pharmacokinetic modeling of non-linear brain distribution of fluvoxamine in the rat.

Geldof M, Freijer J, van Beijsterveldt L, Danhof M - Pharm. Res. (2007)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmacology, Leiden-Amsterdam Center for Drug Research, Leiden University, PO Box 9502, 2300 RA, Leiden, The Netherlands.

ABSTRACT

Introduction: A pharmacokinetic (PK) model is proposed for estimation of total and free brain concentrations of fluvoxamine.

Materials and 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.

Analysis: 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.

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Fluvoxamine concentration-time profiles in ECF (a) and total brain (b), obtained after a 30-min intravenous infusion in Wistar rats. Depicted are the observed fluvoxamine concentrations (dots), the model-simulated upper limit of the interquantile concentration range (90%, upper dashed line), the model simulated lower limit of the interquantile concentration range (10%, lower dashed line), the median concentration (solid line) versus time. A number of 2,000 datasets were simulated from the final PK parameter estimates.
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Fig2: Fluvoxamine concentration-time profiles in ECF (a) and total brain (b), obtained after a 30-min intravenous infusion in Wistar rats. Depicted are the observed fluvoxamine concentrations (dots), the model-simulated upper limit of the interquantile concentration range (90%, upper dashed line), the model simulated lower limit of the interquantile concentration range (10%, lower dashed line), the median concentration (solid line) versus time. A number of 2,000 datasets were simulated from the final PK parameter estimates.

Mentions: In Fig. 2, observed fluvoxamine concentrations in ECF (a) and total brain (b) are depicted as well as the upper and lower limit of interquantile range and the median concentration versus time for a number of 2,000 datasets that were simulated from the obtained PK parameter estimates. Fluvoxamine was transported rapidly into the brain and maximal ECF and brain concentrations were observed only about 20 min later than maximal plasma fluvoxamine concentration. Since maximum concentrations in ECF and brain were observed at the same time after administration, distribution between fluvoxamine in ECF and total brain was very rapid. Furthermore, fluvoxamine concentration-time curves in ECF and brain showed the same kinetic profiles without any delay or different elimination kinetics (Fig. 2).Fig. 2


Pharmacokinetic modeling of non-linear brain distribution of fluvoxamine in the rat.

Geldof M, Freijer J, van Beijsterveldt L, Danhof M - Pharm. Res. (2007)

Fluvoxamine concentration-time profiles in ECF (a) and total brain (b), obtained after a 30-min intravenous infusion in Wistar rats. Depicted are the observed fluvoxamine concentrations (dots), the model-simulated upper limit of the interquantile concentration range (90%, upper dashed line), the model simulated lower limit of the interquantile concentration range (10%, lower dashed line), the median concentration (solid line) versus time. A number of 2,000 datasets were simulated from the final PK parameter estimates.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2279155&req=5

Fig2: Fluvoxamine concentration-time profiles in ECF (a) and total brain (b), obtained after a 30-min intravenous infusion in Wistar rats. Depicted are the observed fluvoxamine concentrations (dots), the model-simulated upper limit of the interquantile concentration range (90%, upper dashed line), the model simulated lower limit of the interquantile concentration range (10%, lower dashed line), the median concentration (solid line) versus time. A number of 2,000 datasets were simulated from the final PK parameter estimates.
Mentions: In Fig. 2, observed fluvoxamine concentrations in ECF (a) and total brain (b) are depicted as well as the upper and lower limit of interquantile range and the median concentration versus time for a number of 2,000 datasets that were simulated from the obtained PK parameter estimates. Fluvoxamine was transported rapidly into the brain and maximal ECF and brain concentrations were observed only about 20 min later than maximal plasma fluvoxamine concentration. Since maximum concentrations in ECF and brain were observed at the same time after administration, distribution between fluvoxamine in ECF and total brain was very rapid. Furthermore, fluvoxamine concentration-time curves in ECF and brain showed the same kinetic profiles without any delay or different elimination kinetics (Fig. 2).Fig. 2

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmacology, Leiden-Amsterdam Center for Drug Research, Leiden University, PO Box 9502, 2300 RA, Leiden, The Netherlands.

ABSTRACT

Introduction: A pharmacokinetic (PK) model is proposed for estimation of total and free brain concentrations of fluvoxamine.

Materials and 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.

Analysis: 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.

Show MeSH