Decrease in brain distribution of fluvoxamine in experimental hyperlipidemic rats.
OBJECTIVE
Many clinical reports and trials have suggested that fluvoxamine (FLV) reduces plasma lipoprotein levels. However, few studies have reported the effect of plasma lipoproteins on FLV pharmacokinetics. The aim of the present study was to investigate the affinities of FLV to plasma lipoproteins and the effect of plasma lipoproteins on the biodistribution of FLV using an experimental hyperlipidemic (HL) rat model.


METHODS
HL rats were prepared by intraperitoneal administration of Poloxamer-407 solution (1.0 g/kg). In vitro protein binding and distribution of FLV in plasma lipoproteins were determined in control and HL rats. In vivo pharmacokinetic study (intravenous administration of FLV, 5.0 mg/kg) and biodistribution analysis for brain and liver at a steady state (infusion, 1.5 mg/kg/hr, 6 hrs) were also performed.


RESULTS
The plasma protein binding of FLV was around 83% and 95% in control and HL rats, respectively, whereas the FLV recoveries in triglyceride-rich lipoprotein fractions were increased in HL. Therefore, the elevation of lipoproteins was likely responsible for the increase in protein binding in HL. After intravenous administration, the area under the plasma concentration vs. time curve (AUC) in HL was 3.9-fold greater than that in control rats, whereas the distribution ratio of FLV plasma concentration to the brain at a steady state was decreased to approximately 20% of that of the control.


CONCLUSIONS
FLV has an affinity to plasma lipoproteins, and their elevation might decrease the FLV biodistribution to brain; the plasma lipoprotein levels could not be found to correlate positively with the FLV pharmacokinetic effect in brain, but rather may attenuate it.
Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Hyogo, Japan. keizo@pharm.kobegakuin.ac.jp
Keizo
K
Fukushima
Shinji
S
Kobuchi
Masakazu
M
Shibata
Kanji
K
Takada
Nobuyuki
N
Sugioka
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D016666:Fluvoxamine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006949:Hyperlipidemias / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D007275:Injections, Intravenous; D016014:Linear Models; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D020442:Poloxamer; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014280:Triglycerides / Q000097:blood
D016666:Fluvoxamine; D008074:Lipoproteins; D020442:Poloxamer; D017367:Selective Serotonin Reuptake Inhibitors; D014280:Triglycerides