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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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Schematic representation of the proposed pharmacokinetic model for fluvoxamine in brain. The fluvoxamine plasma concentration versus time profiles were predicted by a previously developed population PK model and served as input function for fluvoxamine in the brain. The catenary brain distribution model consists of a shallow perfusion-limited brain compartment and a deep brain compartment. The mass exchange of fluvoxamine between these compartments is composed of a passive diffusion term and an saturable active removal flux (k10 = elimination rate constant from central plasma compartment; kin = rate constant for distribution into the shallow brain compartment; kout = rate constant for distribution from the shallow brain compartment; kdiff = diffusion rate constant between the shallow perfusion-limited and the deep brain compartment; CSP = concentration in shallow perfusion-limited compartment; CDB = concentration in deep brain compartment; Nmax = maximal active removal flux; C50 = fluvoxamine concentration in the deep brain compartment at which 50% of saturation of the active removal flux is reached).
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Fig1: Schematic representation of the proposed pharmacokinetic model for fluvoxamine in brain. The fluvoxamine plasma concentration versus time profiles were predicted by a previously developed population PK model and served as input function for fluvoxamine in the brain. The catenary brain distribution model consists of a shallow perfusion-limited brain compartment and a deep brain compartment. The mass exchange of fluvoxamine between these compartments is composed of a passive diffusion term and an saturable active removal flux (k10 = elimination rate constant from central plasma compartment; kin = rate constant for distribution into the shallow brain compartment; kout = rate constant for distribution from the shallow brain compartment; kdiff = diffusion rate constant between the shallow perfusion-limited and the deep brain compartment; CSP = concentration in shallow perfusion-limited compartment; CDB = concentration in deep brain compartment; Nmax = maximal active removal flux; C50 = fluvoxamine concentration in the deep brain compartment at which 50% of saturation of the active removal flux is reached).

Mentions: The proposed model for the brain distribution kinetics of fluvoxamine is an extension of a model proposed earlier for the brain distribution of thiopental (14,17) and is illustrated in Fig. 1. The brain distribution model consists of three compartments to describe the concentration versus time profile in plasma in combination with a catenary two compartment model to describe the distribution of fluvoxamine into the brain. Within the catenary model, the first brain compartment is a shallow compartment that is in direct contact with the blood flow and where the concentration is determined by perfusion (shallow perfusion-limited compartment). The second compartment is a deep brain compartment in which the concentration is equal to the measured ECF concentrations (deep brain compartment). Fluvoxamine is not able to enter the deep brain compartment directly, but only indirectly from the shallow perfusion-limited compartment. The transport between the two brain compartments is by diffusion and/or active transport (influx and/or efflux) mediated by P-glycoprotein (Pgp) and/or other transporters. Therefore, the distribution of fluvoxamine into the brain is determined by perfusion of the outer shallow brain tissues (subscript SP) and exchange with the deep brain compartment (subscript DB):1\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$ \frac{{dA_{{{\text{sp}}}} }} {{dt}} = Q_{{\text{B}}} C_{{i{\text{n}}}} - Q_{{\text{B}}} C_{{{\text{out}}}} + N_{{{\text{SP - DB}}}} $$\end{document}2\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$ \frac{{dA_{{{\text{DB}}}} }} {{dt}} = - N_{{{\text{SP - DB}}}} $$\end{document}in which ASP is the amount of fluvoxamine in the shallow perfusion-limited compartment, QB is the effective plasma perfusion rate, Cin is the concentration entering the shallow perfusion-limited compartment, Cout is the concentration leaving the shallow perfusion-limited compartment, NSP-DB is the net mass exchange between the shallow perfusion-limited compartment and deep brain compartment and ADB is the amount of fluvoxamine in the deep brain compartment.Fig. 1


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

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

Schematic representation of the proposed pharmacokinetic model for fluvoxamine in brain. The fluvoxamine plasma concentration versus time profiles were predicted by a previously developed population PK model and served as input function for fluvoxamine in the brain. The catenary brain distribution model consists of a shallow perfusion-limited brain compartment and a deep brain compartment. The mass exchange of fluvoxamine between these compartments is composed of a passive diffusion term and an saturable active removal flux (k10 = elimination rate constant from central plasma compartment; kin = rate constant for distribution into the shallow brain compartment; kout = rate constant for distribution from the shallow brain compartment; kdiff = diffusion rate constant between the shallow perfusion-limited and the deep brain compartment; CSP = concentration in shallow perfusion-limited compartment; CDB = concentration in deep brain compartment; Nmax = maximal active removal flux; C50 = fluvoxamine concentration in the deep brain compartment at which 50% of saturation of the active removal flux is reached).
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Fig1: Schematic representation of the proposed pharmacokinetic model for fluvoxamine in brain. The fluvoxamine plasma concentration versus time profiles were predicted by a previously developed population PK model and served as input function for fluvoxamine in the brain. The catenary brain distribution model consists of a shallow perfusion-limited brain compartment and a deep brain compartment. The mass exchange of fluvoxamine between these compartments is composed of a passive diffusion term and an saturable active removal flux (k10 = elimination rate constant from central plasma compartment; kin = rate constant for distribution into the shallow brain compartment; kout = rate constant for distribution from the shallow brain compartment; kdiff = diffusion rate constant between the shallow perfusion-limited and the deep brain compartment; CSP = concentration in shallow perfusion-limited compartment; CDB = concentration in deep brain compartment; Nmax = maximal active removal flux; C50 = fluvoxamine concentration in the deep brain compartment at which 50% of saturation of the active removal flux is reached).
Mentions: The proposed model for the brain distribution kinetics of fluvoxamine is an extension of a model proposed earlier for the brain distribution of thiopental (14,17) and is illustrated in Fig. 1. The brain distribution model consists of three compartments to describe the concentration versus time profile in plasma in combination with a catenary two compartment model to describe the distribution of fluvoxamine into the brain. Within the catenary model, the first brain compartment is a shallow compartment that is in direct contact with the blood flow and where the concentration is determined by perfusion (shallow perfusion-limited compartment). The second compartment is a deep brain compartment in which the concentration is equal to the measured ECF concentrations (deep brain compartment). Fluvoxamine is not able to enter the deep brain compartment directly, but only indirectly from the shallow perfusion-limited compartment. The transport between the two brain compartments is by diffusion and/or active transport (influx and/or efflux) mediated by P-glycoprotein (Pgp) and/or other transporters. Therefore, the distribution of fluvoxamine into the brain is determined by perfusion of the outer shallow brain tissues (subscript SP) and exchange with the deep brain compartment (subscript DB):1\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$ \frac{{dA_{{{\text{sp}}}} }} {{dt}} = Q_{{\text{B}}} C_{{i{\text{n}}}} - Q_{{\text{B}}} C_{{{\text{out}}}} + N_{{{\text{SP - DB}}}} $$\end{document}2\documentclass[12pt]{minimal}\usepackage{amsmath}\usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy}\usepackage{mathrsfs}\usepackage{upgreek}\setlength{\oddsidemargin}{-69pt}\begin{document}$$ \frac{{dA_{{{\text{DB}}}} }} {{dt}} = - N_{{{\text{SP - DB}}}} $$\end{document}in which ASP is the amount of fluvoxamine in the shallow perfusion-limited compartment, QB is the effective plasma perfusion rate, Cin is the concentration entering the shallow perfusion-limited compartment, Cout is the concentration leaving the shallow perfusion-limited compartment, NSP-DB is the net mass exchange between the shallow perfusion-limited compartment and deep brain compartment and ADB is the amount of fluvoxamine in the deep brain compartment.Fig. 1

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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