title: Pharmacokinetic modeling of non-linear brain distribution of fluvoxamine in the rat.
abstract: 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.
authors: Division of Pharmacology, Leiden-Amsterdam Center for Drug Research, Leiden University, PO Box 9502, 2300 RA, Leiden, The Netherlands.
authors: Marian
authors: M
authors: Geldof
authors: Jan
authors: J
authors: Freijer
authors: Ludy
authors: L
authors: van Beijsterveldt
authors: Meindert
authors: M
authors: Danhof
mesh_terms: 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*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D016666:Fluvoxamine; D017367:Selective Serotonin Reuptake Inhibitors
references: Clin Pharmacokinet. 2003;42(12):997-1022
references: 12959633
references: Eur Neuropsychopharmacol. 1999 Jul;9 Suppl 3:S101-6
references: 10523065
references: Clin Pharmacol Ther. 2001 Mar;69(3):89-95
references: 11240971
references: Clin Cardiol. 1991 Aug;14(8):696-8
references: 1914276
references: Brain Res Brain Res Rev. 1997 Sep 30;25(1):27-49
references: 9370049
references: Br J Pharmacol. 2007 Jul;151(5):713-20
references: 17471181
references: Br J Pharmacol. 1995 Jun;115(3):503-9
references: 7582464
references: Eur J Pharmacol. 1992 Dec 8;229(1):101-3
references: 1282104
references: Eur J Pharm Sci. 2007 Jan;30(1):45-55
references: 17134886
references: Pharm Res. 2002 Oct;19(10):1537-43
references: 12425473
references: Clin Pharmacol Ther. 1994 Sep;56(3):248-52
references: 7924119
references: Life Sci. 1994;55(3):163-7
references: 8007758
references: J Pharmacokinet Biopharm. 1982 Feb;10(1):53-75
references: 7069578
references: Pharm Res. 2005 Sep;22(9):1432-7
references: 16132354
references: J Neurosci. 1999 Dec 1;19(23):10494-501
references: 10575045
references: J Pharm Sci. 2004 Dec;93(12):3027-38
references: 15503315
references: Neuropharmacology. 1995 May;34(5):501-8
references: 7566484
references: J Neurosci Methods. 1980 Dec;3(2):129-49
references: 6110810
references: Annu Rev Pharmacol Toxicol. 2007;47:357-400
references: 17067280
references: J Neurochem. 1989 Aug;53(2):652-4
references: 2568406
references: Eur J Pharm Sci. 2007 Nov;32(3):200-8
references: 17825539
references: Br J Clin Pharmacol. 1997 Sep;44(3):219-25
references: 9296315
references: Anesthesiology. 2000 Oct;93(4):1085-94
references: 11020765
references: Pharm Res. 1998 Nov;15(11):1673-9
references: 9833986
references: J Pharmacol Exp Ther. 2003 Apr;305(1):197-204
references: 12649369
references: Br J Pharmacol. 2007 Jul;151(5):701-12
references: 17471182
references: Anesthesiology. 2001 Apr;94(4):566-73
references: 11379674
references: Eur J Clin Pharmacol. 1992;43(3):289-94
references: 1425894
references: J Pharmacol Exp Ther. 1998 Jan;284(1):202-7
references: 9435179
references: J Pharmacol Exp Ther. 1997 Nov;283(2):809-16
references: 9353402
references: J Pharmacol Exp Ther. 2002 Dec;303(3):1029-37
references: 12438524
references: J Neurochem. 1996 Aug;67(2):669-76
references: 8764594
references: Adv Drug Deliv Rev. 2000 Dec 15;45(2-3):283-94
references: 11108980
references: Am Fam Physician. 2003 Feb 1;67(3):547-54
references: 12588077