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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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Goodness-of-fit plots of fluvoxamine concentrations in ECF and total brain obtained for the physiological PK model. Depicted are scatter plots of the observed fluvoxamine ECF concentrations versus the individual model predictions (a) and population model predictions (b) and observed fluvoxamine brain concentrations versus the individual model predictions (c) and population model predictions (d). The limit of quantification (1 ng.ml−1) is added for clarity (dashed line).
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Fig4: Goodness-of-fit plots of fluvoxamine concentrations in ECF and total brain obtained for the physiological PK model. Depicted are scatter plots of the observed fluvoxamine ECF concentrations versus the individual model predictions (a) and population model predictions (b) and observed fluvoxamine brain concentrations versus the individual model predictions (c) and population model predictions (d). The limit of quantification (1 ng.ml−1) is added for clarity (dashed line).

Mentions: The coefficients of variation (C.V.) for the ECF and brain parameters were lower than 33% for al parameters, except for C50 and for which the coefficients of variation were 96.8 and 92.5%, respectively. This can be explained by the fact that full saturation of the efflux transporter was not reached in the present investigation. Inter-individual variability (IIV) for kin was equal to 0.50 and for kout equal to 0.17. Inter-individual variability in the other parameters could not be adequately estimated and was fixed to zero. Correlation between the variability in the estimated PK parameters was observed for kin and kout and was implemented in the model. In Fig. 4, goodness-of-fit plots for fluvoxamine concentrations in ECF of the frontal cortex and total brain are depicted. Observed ECF concentrations were in close agreement with individual predicted (a) and population predicted (b) ECF concentrations. No substantial or systemic deviation from the identity line was observed indicating adequate description of observed fluvoxamine ECF concentrations. Furthermore, no substantial or systemic deviation from the identity line was present for the observed fluvoxamine brain concentrations vs. individual (C) and population (D) predicted brain concentrations. Although each observation from total brain was collected from a different animal by destructive sampling, fluvoxamine brain concentrations could be adequately described.Fig. 4


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

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

Goodness-of-fit plots of fluvoxamine concentrations in ECF and total brain obtained for the physiological PK model. Depicted are scatter plots of the observed fluvoxamine ECF concentrations versus the individual model predictions (a) and population model predictions (b) and observed fluvoxamine brain concentrations versus the individual model predictions (c) and population model predictions (d). The limit of quantification (1 ng.ml−1) is added for clarity (dashed line).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2279155&req=5

Fig4: Goodness-of-fit plots of fluvoxamine concentrations in ECF and total brain obtained for the physiological PK model. Depicted are scatter plots of the observed fluvoxamine ECF concentrations versus the individual model predictions (a) and population model predictions (b) and observed fluvoxamine brain concentrations versus the individual model predictions (c) and population model predictions (d). The limit of quantification (1 ng.ml−1) is added for clarity (dashed line).
Mentions: The coefficients of variation (C.V.) for the ECF and brain parameters were lower than 33% for al parameters, except for C50 and for which the coefficients of variation were 96.8 and 92.5%, respectively. This can be explained by the fact that full saturation of the efflux transporter was not reached in the present investigation. Inter-individual variability (IIV) for kin was equal to 0.50 and for kout equal to 0.17. Inter-individual variability in the other parameters could not be adequately estimated and was fixed to zero. Correlation between the variability in the estimated PK parameters was observed for kin and kout and was implemented in the model. In Fig. 4, goodness-of-fit plots for fluvoxamine concentrations in ECF of the frontal cortex and total brain are depicted. Observed ECF concentrations were in close agreement with individual predicted (a) and population predicted (b) ECF concentrations. No substantial or systemic deviation from the identity line was observed indicating adequate description of observed fluvoxamine ECF concentrations. Furthermore, no substantial or systemic deviation from the identity line was present for the observed fluvoxamine brain concentrations vs. individual (C) and population (D) predicted brain concentrations. Although each observation from total brain was collected from a different animal by destructive sampling, fluvoxamine brain concentrations could be adequately described.Fig. 4

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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