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. 2011;88(1-2):44-9.
doi: 10.1159/000329417. Epub 2011 Jul 14.

Pharmacokinetics of fluoxetine in rhesus macaques following multiple routes of administration

E K Sawyer  1 , L L Howell
Affiliations

Pharmacokinetics of fluoxetine in rhesus macaques following multiple routes of administration

E K Sawyer et al. Pharmacology. 2011.

Abstract

Background/aims: Fluoxetine (Prozac) is a selective serotonin reuptake inhibitor currently used to treat depression and mood disorders. It has been widely studied clinically and preclinically, yet there is limited knowledge of its pharmacokinetics in nonhuman primates.

Methods: The present study characterized the pharmacokinetics of fluoxetine and its active metabolite norfluoxetine in rhesus macaques following both acute (1, 3, 5.6 and 10 mg/kg) and chronic doses (5.6 and 10 mg/kg/day) via different routes of administration (intravenous, subcutaneous, intramuscular, and oral). Blood samples were collected at multiple time points following administration and analyzed using mass spectrometry.

Results: Fluoxetine had a half-life of 11-16 h and norfluoxetine had a half-life of 21-29 h. Potentially functionally significant serum concentrations of norfluoxetine were present at 24 h even after a single administration of fluoxetine. Similar to observations in humans under steady state conditions, norfluoxetine accounted for the greater percentage of active drug in the blood stream.

Conclusion: A daily dose of 10 mg/kg administered orally maintained serum concentrations in the human clinical range over the course of 6 weeks. Given the long half-lives of fluoxetine and norfluoxetine observed in this study, precautions should be taken when designing preclinical studies to prevent accumulation of drug serum concentrations.

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Figures

Fig. 1
Fig. 1
Serum concentrations of total fluoxetine, fluoxetine, and norfluoxetine, following acute i.m. administration (n = 2). a Total fluoxetine serum concentrations following administration of 1.0, 3.0 and 5.6 mg/kg fluoxetine are dose dependent and relatively stable, with significant active drug remaining 24 h after a single i.m. injection. b Fluoxetine, norfluoxetine, and total drug concentration following administration of 10.0 mg/kg. Fluoxetine levels rapidly rise and reach the human clinical range; norfluoxetine levels do not significantly contribute during the first 120 min following injection. Dashed lines indicate the human clinical range.
Fig. 2
Fig. 2
Serum concentrations of fluoxetine and norfluoxetine following an acute 5.6 mg/kg i.m. injection of fluoxetine (n = 2). As concentrations of fluoxetine fall, concentrations of norfluoxetine rise, resulting in a fairly consistent concentration of active drug in the blood.
Fig. 3
Fig. 3
Serum concentrations during and after 6-day administration of 5.6 mg/kg fluoxetine HCl s.c. or p.o. Concentrations steadily rise during administration and decline following cessation of treatment. Subcutaneous administration results in significantly higher serum concentrations. Both methods result in steady-state concentrations in the clinical range for humans. Dashed lines indicate the human clinical range.
Fig. 4
Fig. 4
Serum concentrations during 6-week chronic fluoxetine administration (10 mg/kg p.o.; n = 5). Serum concentrations are stable between weeks 3 and 6 and are maintained within the human clinical range for the duration of administration. Washout measurements were taken 1 week after the cessation of treatment. Dashed lines indicate the human clinical range.
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