title: Pharmacokinetics of fluoxetine in rhesus macaques following multiple routes of administration.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Neuroscience Program, Emory University, Atlanta, GA, USA.
authors.forename: E K
authors.initials: EK
authors.lastname: Sawyer
authors.forename: L L
authors.initials: LL
authors.lastname: Howell
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004353:Drug Evaluation, Preclinical; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007279:Injections, Subcutaneous; D008253:Macaca mulatta; D051379:Mice; D023421:Models, Animal; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D013045:Species Specificity; D013997:Time Factors
chemical_list: D000928:Antidepressive Agents; D005473:Fluoxetine; D017367:Selective Serotonin Reuptake Inhibitors; C036139:norfluoxetine