Clinical Pharmacokinetics

, Volume 26, Issue 3, pp 201–214 | Cite as

Clinical Pharmacokinetics of Fluoxetine

  • Alfredo C. Altamura
  • Anna R. Moro
  • Mauro Percudani
Review Article Drug Disposition

Summary

Fluoxetine is well absorbed after oral intake, is highly protein bound, and has a large volume of distribution. The elimination half-life of fluoxetine is about 1 to 4 days, while that of its metabolite norfluoxetine ranges from 7 to 15 days.

Fluoxetine has a nonlinear pharmacokinetic profile. Therefore, the drug should be used with caution in patients with a reduced metabolic capability (i.e. hepatic dysfunction).

In contrast with its effect on the pharmacokinetics of other antidepressants, age does not affect fluoxetine pharmacokinetics. This finding together with the better tolerability profile of fluoxetine (compared with tricyclic antidepressants) makes this drug particularly suitable for use in elderly patients with depression. Furthermore, the pharmacokinetics of fluoxetine are not affected by either obesity or renal impairment.

On the basis of results of plasma concentration-clinical response relationship studies, there appears to be a therapeutic window for fluoxetine. Concentrations of fluoxetine plus norfluoxetine above 500 µg/L appear to be associated with a poorer clinical response than lower concentrations.

Fluoxetine interacts with some other drugs. Concomitant administration of fluoxetine increased the blood concentrations of antipsychotics or antidepressants. The interactions between fluoxetine and lithium, tryptophan and monoamine oxidase inhibitors, in particular, are potentially serious, and can lead to the ‘serotonergic syndrome’. This is because of synergistic pharmacodynamic effects and the influence of fluoxetine on the bioavailability of these compounds.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Altamura AC. Drug resistance phenomena in major psychoses: their discrimination and causal mechanisms. Clinical Neuropharmacology 13 (Suppl. 1): 1–15, 1990CrossRefGoogle Scholar
  2. Altamura AC. Drug-resistance in major depression: definition, discrimination and possible pharmacological strategies. In Meitzer & Nerozzi (Eds) Current practices and future developments in the pharmacotherapy of mental disorders, pp. 139–148, Excerpta Medica, Amsterdam, 1991Google Scholar
  3. Altamura AC, De Novellis P, Guercetti G, Invernizzi G, Percudani M, et al. Fluoxetine compared with amitriptyline in elderly depression: a controlled clinical trial. International Journal of Clinical Pharmacological Research 9: 391–396, 1989Google Scholar
  4. Altamura AC, Mauri MC. Aspects of treatment of elderly depression: the fluoxetine experience. In Freeman (Ed.) The use of fluoxetine in clinical practice, Vol. 183, pp. 53–59, Royal Society of Medicine Services, London, New York, 1991Google Scholar
  5. Altamura AC, Melorio T, Invernizzi G, Colacurcio F, Gomeni R. Age-related differences in kinetics and side-effects of viloxazine in man and their clinical implications. Psychopharmacology 81: 281–285, 1983PubMedCrossRefGoogle Scholar
  6. Altamura AC, Melorio T, Invernizzi G, Gomeni R. Influence of age on mianserin pharmacokinetics. Psychopharmacology 78: 380–382, 1982PubMedCrossRefGoogle Scholar
  7. Altamura AC, Montgomery SA. Fluoxetine dose, pharmacokinetics and clinical efficacy. Reviews in Contemporary Pharmacotherapy 1: 75–81, 1990Google Scholar
  8. Altamura AC, Montgomery SA, Wernicke JF. The evidence for 20 mg a day fluoxetine as the optimal dose in the treatment of depression. British Journal of Psychiatry 153 (Suppl. 3): 103–106, 1988Google Scholar
  9. Altamura AC, Percudani M. The use of antidepressants for long-term treatment of recurrent depression: rationale, current methodologies, and future directions. Journal of Clinical Psychiatry 54 (Suppl. 8): 29–37, 1993PubMedGoogle Scholar
  10. Aronoff GR, Bergstrom RF, Pottratz ST, Sloan RS, Wolen RL, et al. Fluoxetine kinetics and protein binding in normal and impaired renal function. Clinical Pharmacology and Therapeutics 36: 138–144, 1984PubMedCrossRefGoogle Scholar
  11. Baldessarini RJ, Centorrino F, Flood JG, Volpicelli SA, Huston-Lyons D, et al. Tissue concentrations of clozapine and its metabolites in the rat. Neuropsychopharmacology 9: 117–124, 1993PubMedGoogle Scholar
  12. Baron B, Ogden A, Siegel B, Stegeman J, Ursillo R, et al. Rapid downregulation of beta-adrenoceptors by coadministration of desipramine and fluoxetine. European Journal of Pharmacology 164: 125–134, 1988CrossRefGoogle Scholar
  13. Beasley Jr CM, Bosomworth JC, Wernick JF. Fluoxetine: relationships among dose, response, adverse events, and plasma concentrations in the treatment of depression. Psychopharmacology Bulletin 26: 18–24, 1990PubMedGoogle Scholar
  14. Beasley CM, Masica DN, Potvin JH. Fluoxetine: a review of receptor and functional effects and their clinical implications. Psychopharmacology 107: 1–10, 1992PubMedCrossRefGoogle Scholar
  15. Benfield P, Heel RC, Lewis SP. Fluoxetine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs 32: 481–508, 1986PubMedCrossRefGoogle Scholar
  16. Bergstrom R, Wolen RL, Dhahir P, Hatcher B, Werner N, et al. Effect of food on the absorption of fluoxetine in normal subjects. Abstracts of the American Pharmaceutical Association Academy of Pharmaceutical Sciences 14: 110, 1984Google Scholar
  17. Bergstrom RF, Farid KZ, McClurg JE, Lemberger L. The pharmacokinetics of fluoxetine in elderly subjects. II World Conference on Clinical Pharmacology and Therapeutics, Washington, 31 July–5 August, 1983. Abstract no. 699, p. 120, 1983Google Scholar
  18. Bergstrom RF, Lemberger L, Farid NA, Wolen RL. Clinical pharmacology and pharmacokinetics of fluoxetine: a review. British Journal of Psychiatry 153 (Suppl. 3): 47–50, 1988Google Scholar
  19. Bergstrom RF, Peyton AL, Lemberger L. Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction. Clinical Pharmacology and Therapeutics 51 (3): 239–248, 1992PubMedCrossRefGoogle Scholar
  20. Bergstrom RF, vanLier RBL, Lemberger L, Tenbarge JL. Absolute bioavailability of fluoxetine in beagle dogs. Abstracts of the American Pharmaceutical Association Academy of Pharmaceutical Sciences 16: 126, 1986aGoogle Scholar
  21. Bergstrom RF, Wolen RL, Lemberger L, Dhahir P, Barrett JL. Fluoxetine single dose-multiple dose kinetics. 39th National Meeting of the American Pharmaceutical Association Academy of Pharmaceutical Sciences, Washington, 1985. Vol. 15, p. 137, 1985Google Scholar
  22. Bergstrom RF, Wolen RL, Lemberger L, Tenbarge JL, Masco HL. Fluoxetine steady state pharmacokinetics in depressed patients. 133rd Annual Meeting of the American Pharmaceutical Association, San Francisco, 16–20 March, 1986. Vol. 16, No. 1, Abstract no. P55, 1986bGoogle Scholar
  23. Bloomer JC, Woods FR, Haddock RE, Lennard MS, Tucker GT. The role of cytochrome P4502D6 in the metabolism of paroxetine by human liver microsomes. British Journal of Clinical Pharmacology 33: 521–523, 1992PubMedCrossRefGoogle Scholar
  24. Bodkin JA, Teicher MH. Fluoxetine may antagonize the anxiolytic action of buspirone. Journal of Clinical Psychopharmacology 9: 150, 1989PubMedCrossRefGoogle Scholar
  25. Boyer WF, Feighner JP. Pharmacokinetics and drug interactions. In Feighner & Boyer (Eds) Selective serotonin reuptake inhibitors, pp. 81–88, J. Wiley and Sons, New York, 1991Google Scholar
  26. Brøsen K, Gram IF, Sindrup S, et al. Pharmacogenetics of tricyclics and novel antidepressants: recent developments. Clinical Neuropharmacology 15 (Suppl. 1): 80–81, 1992CrossRefGoogle Scholar
  27. Brøsen K, Skjelbo E. Fluoxetine and norfluoxetine are potent inhibitors of P450IID6 — the source of the sparteine/debrisoquine oxidation polymorphism. British Journal of Clinical Pharmacology 32: 136–137, 1991PubMedCrossRefGoogle Scholar
  28. Byerley WF, McConnell EJ, McCabe RT, Dawson TM, Grosser BI, et al. Decreased beta-adrenergic receptors in rat brain after chronic administration of the selective serotonin uptake inhibitor fluoxetine. Psychopharmacology 94: 141–143, 1988PubMedCrossRefGoogle Scholar
  29. Cassady SL, Thaker GK. Addition of fluoxetine to clozapine. American Journal of Psychiatry 149: 1274, 1992PubMedGoogle Scholar
  30. Centorrino F, Baldessarini RJ, Kondo J, Frankenburg FR, Volpicelli SA, et al. Serum concentrations of clozapine and its metabolites: effects of cotreatment with valproate or fluoxetine. American Journal of Psychiatry 151: 123–125, 1994PubMedGoogle Scholar
  31. Ciraulo DA, Shader RI. Fluoxetine drug-drug interactions: I. Antidepressants and antipsychotics. Journal of Clinical Psychopharmacology 10: 48–50, 1990PubMedCrossRefGoogle Scholar
  32. Committee on Safety of Medicines. Fluvoxamine and fluoxetine — interaction with monoamine oxidase inhibitors, lithium and tryptophan. Current Problems No. P26: 1989Google Scholar
  33. Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE. The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. British Journal of Clinical Pharmacology 34: 262–265, 1992PubMedCrossRefGoogle Scholar
  34. De Vane CL. Pharmacokinetics of the selective serotonin reuptake inhibitors. Journal of Clinical Psychiatry 53 (Suppl.): 13–20, 1991Google Scholar
  35. Dixit V, Nguyen H, Dixit VM. Solid-phase extraction of fluoxetine and norfluoxetine from serum with gas chromatography-electron-capture detection. Journal of Chromatography 563: 379–384, 1991PubMedCrossRefGoogle Scholar
  36. Dumbrille-Ross A, Tang SW. Manipulations of synaptic serotonin: discrepancy of effects on serotonin S1 and S2 sites. Life Science 32: 2677–2684, 1983CrossRefGoogle Scholar
  37. Eisen A. Fluoxetine and desipramine: a strategy for augmenting antidepressant response. Pharmacopsychiatry 22: 272–273, 1989PubMedCrossRefGoogle Scholar
  38. Farid NA, Bergstrom RF, Lemberger L, Ziege EA, Tenbarge J, et al. Studies on disposition of fluoxetine and radioactive isotopes. 15th Collegium International Neuro-Psychopharmacologicum Congress, Puerto Rico, 1986Google Scholar
  39. Fichtner CG, Johe LH, Braun BG. Does fluoxetine have a therapeutic window? Lancet 7: 520–521, 1991CrossRefGoogle Scholar
  40. Fuller RW, Wong DT. Serotonin re-uptake blockers in vitro and in vivo. Journal of Clinical Psychopharmacology 7: 365–435, 1987CrossRefGoogle Scholar
  41. Goff DC, Brotman AW, Waites RN, McCormick S. Trial of fluoxetine added to neuroleptics for treatment-resistant schizophrenic patients. American Journal of Psychiatry 147: 492–494, 1990PubMedGoogle Scholar
  42. Goff DC, Midha KK, Brotman AW, Waites M, Baldessarini RJ. Elevation of plasma concentrations of haloperidol after the addition of fluoxetine. American Journal of Psychiatry 148: 790–792, 1991PubMedGoogle Scholar
  43. Goodnick PJ. Influence of fluoxetine on plasma levels of desipramine. American Journal of Psychiatry 146: 552, 1989PubMedGoogle Scholar
  44. Goodnick PJ. Pharmacokinetics of second generation antidepressant: fluoxetine. Psychopharmacology Bulletin 27: 503–512, 1991PubMedGoogle Scholar
  45. Greenblatt DJ, Preskorn SH, Cotreau MM, Horst WD, Harmatz JS. Fluoxetine impairs clearance of alprazolam but not of clonazepam. Clinical Pharmacology and Therapeutics 52: 479–486, 1992PubMedCrossRefGoogle Scholar
  46. Grimsley SR, Jann MW, Carter JG, Mello AP, Souza MJ. Increased carbamazepine plasma concentrations after fluoxetine coadministration. Clinical Pharmacology and Therapeutics 50: 10–15, 1991PubMedCrossRefGoogle Scholar
  47. Hansen TE, Dieter K, Keepers GA. Interaction of fluoxetine and pentazocine. American Journal of Psychiatry 147: 949–950, 1990PubMedGoogle Scholar
  48. Jarvis MR. Clinical pharmacokinetics of tricyclic antidepressant overdose. Psychopharmacology Bulletin 27: 541–550, 1991PubMedGoogle Scholar
  49. Kelly MW, Perry PJ, Holstad SG, Garvey MJ. Serum fluoxetine and norfluoxetine concentrations and antidepressant response. Therapeutic Drug Monitoring 11: 165–170, 1989PubMedCrossRefGoogle Scholar
  50. Ketai R. Interaction between fluoxetine and neuroleptics. American Journal of Psychiatry 150: 836–837, 1993PubMedGoogle Scholar
  51. Kinkaid RL, McMullin MM, Crookman SB, Riders F. Report of a fluoxetine fatality. Journal of Analytical Toxicology 14: 327–329, 1990Google Scholar
  52. Lasher TA, Fleishaker JC, Steenwyk RC, Antal EJ. Pharmacokinetic pharmacodynamic evaluation of the combined administration of alprazolam and fluoxetine. Psychopharmacology 104: 323–327, 1991PubMedCrossRefGoogle Scholar
  53. Lemberger L, Bergstrom RF, Wolen RL, Farid NA, Enas GG, et al. Fluoxetine: clinical pharmacology and physiologic disposition. Journal of Clinical Psychiatry 46: 14–19, 1985PubMedGoogle Scholar
  54. Lemberger L, Rowe H, Bergstrom RF, Farid KZ, Enas GG. Effect of fluoxetine on psychomotor performance, physiologic response, and kinetics of ethanol. Clinical Pharmacology and Therapeutics 37: 658–664, 1985PubMedCrossRefGoogle Scholar
  55. Lemberger L, Rowe H, Bosomworth JC, Tenbarge JB, Bergstrom RF. The effect of fluoxetine on the pharmacokinetics and psychomotor response of diazepam. Clinical Pharmacology and Therapeutics 43: 413–419, 1988Google Scholar
  56. Lock JD, Gwirtsman HE, Targ EF. Possible adverse drug interactions between fluoxetine and other psychotropics. Journal of Clinical Psychopharmacology 10: 383–384, 1990PubMedCrossRefGoogle Scholar
  57. Martensson B, Nyberg S, Toresson G, Brodin E, Bertilsson L. Fluoxetine treatment of depression. Acta Psychiatrica Scandinavica 79: 586–596, 1989PubMedCrossRefGoogle Scholar
  58. Montgomery SA, Baldwin D, Shah A, Green M, Fineberg N, et al. Fluoxetine treatment of depression. Clinical Neuropharmacology 13 (Suppl. 1): 71–75, 1990CrossRefGoogle Scholar
  59. Montgomery SA, James D, de Ruiter M, et al. Weekly oral fluoxetine treatment of major depressive disorder, controlled trial. 15th Collegium International Neuro-Psychopharmacologicum Congress, Puerto Rico, 1986Google Scholar
  60. Nash JF, Bopp RJ, Carmichaell RH, et al. Determination of fluoxetine and norfluoxetine in plasma by gas chromatography with electron-capture detection. Clinical Chemistry 28: 2100–2102, 1982PubMedGoogle Scholar
  61. Nebert DW, Nelson DR, Coon MJ, Estabrook RW, Feyereisen R, et al. The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature. DNA and Cell Biology 10: 1–4, 1991PubMedCrossRefGoogle Scholar
  62. Nelson JC, Mazure CM, Bowers Jr MB, Jatlow PI. A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Archives of General Psychiatry 48: 303–307, 1991PubMedCrossRefGoogle Scholar
  63. Nichols JH, Charlson JR, Lawson GM. Plasma fluoxetine and norfluoxetine by automated HPLC. Clinical Chemistry 38 (6): 1012, 1992Google Scholar
  64. Nies A, Robinson DS, Friedman MJ, et al. Relationship between age and tricyclic antidepressant plasma levels. American Journal of Psychiatry 134: 790–793, 1977PubMedGoogle Scholar
  65. Orsulak PJ, Kenney JT, Debus JR, Crowley G, Wittman PD. Determination of the antidepressant fluoxetine and its metabolite norfluoxetine in serum by reversed-phase HPLC, with ultraviolet detection. Clinical Chemistry 34: 1875–1878, 1988PubMedGoogle Scholar
  66. Otton SV, Wu D, Joffe RT, Cheung SW, Sellers EM. Inhibition by fluoxetine of cytochrome P450 activity. Clinical Pharmacology & Therapeutics 53: 401–409, 1993CrossRefGoogle Scholar
  67. Potter WZ, Manji HK. Antidepressants, metabolites and apparent drug resistance. Clinical Neuropharmacology (Suppl. 1) 13: 45–53, 1990CrossRefGoogle Scholar
  68. Preskorn SH. Pharmacokinetics of antidepressants: why and how they are relevant to treatment? Journal of Clinical Psychiatry 54 (Suppl.): 2–22, 1993Google Scholar
  69. Preskorn SH, Beber JH, Faul JC, Hirschfeld RMA. Serious adverse effects of combining fluoxetine and tricyclic antidepressants. American Journal of Psychiatry 147: 532, 1990PubMedGoogle Scholar
  70. Renshaw PF, Guimaraes AR, Fava M, Rosenbaum JF, Pearlman JD, et al. Accumulation of fluoxetine and norfluoxetine in human brain during therapeutic administration. American Journal of Psychiatry 149: 1592–1594, 1992PubMedGoogle Scholar
  71. Roethger JR. The importance of blood collection site for determination of basic drugs: a case with fluoxetine and diphenhydramine overdose. Journal of Analytical Toxicology 14: 191–192, 1990Google Scholar
  72. Rohrig TP, Prouty RW. Fluoxetine overdose: a case report. Journal of Analytical Toxicology 13: 305–307, 1989PubMedGoogle Scholar
  73. Rosenthal J, Hemlock C, Hellerstein DJ, Yanowitch P, Kasch K, et al. A preliminary study of serotonergic antidepressants in the treatment of dysthymia. Progress in Neuro-Psychopharmacology and Biological Psychiatry 16: 933–941, 1992PubMedCrossRefGoogle Scholar
  74. Saletu B, Grunberger J. Classification and determination of cerebral bioavailability of fluoxetine: pharmacokinetic, pharmaco-EEG, and psychometric analyses. Journal of Clinical Psychiatry 46: 45–52, 1985PubMedGoogle Scholar
  75. Schenker S, Bergstrom RF, Wolen RL, Lemberger L. Fluoxetine disposition and elimination in cirrhosis. Clinical Pharmacology and Therapeutics 44: 353–359, 1988PubMedCrossRefGoogle Scholar
  76. Sindrup SH, Brosen K, Gram LF, Hallas J, Skjelbo E, et al. The relationship between paroxetine and sparteine oxidation polymorphism. Clinical Pharmacology and Therapeutics 51: 278–287, 1992PubMedCrossRefGoogle Scholar
  77. Sjöqvist F. Pharmacogenetics of antidepressants. In Dahl & Gram (Eds) Clinical pharmacology: psychiatry, pp. 181–191, Springer-Verlag, Berlin, Heidelberg, 1989CrossRefGoogle Scholar
  78. Sommi RW, Crismon ML, Bowden CL. Fluoxetine a serotonin-specific, second-generation antidepressant. Pharmacotherapy 7: 1–15, 1987PubMedGoogle Scholar
  79. Suckow RF, Roose SP, Cooper TB. Effect of fluoxetine on plasma desipramine and 2-hydroxydesipramine. Biological Psychiatry 31: 200–204, 1992aPubMedCrossRefGoogle Scholar
  80. Suckow RF, Zhang MF, Cooper TB. Sensitive and selective liquid-chromatographic assay of fluoxetine and norfluoxetine in plasma with fluorescence detection after precolumn derivatization. Clinical Chemistry 38: 1756–1761, 1992bPubMedGoogle Scholar
  81. Tate JL. Extrapyramidal symptoms in a patient taking haloperidol and fluoxetine. American Journal of Psychiatry 146: 399–400, 1989PubMedGoogle Scholar
  82. van Harten J. Clinical pharmacokinetics of selective serotonin reuptake inhibitors. Clinical Pharmacokinetics 24 (3): 203–220, 1993PubMedCrossRefGoogle Scholar
  83. Vaughan DA. Interaction of fluoxetine with tricyclic antidepressants. American Journal of Psychiatry 145: 1478, 1988PubMedGoogle Scholar
  84. von Ammon Cavanaugh S. Drug-drug interactions of fluoxetine with tricyclics. Psychosomatics 31: 273–276, 1990CrossRefGoogle Scholar
  85. Wamsley JK, Byerley WF, McCabe RT, et al. Receptor alterations associated with serotonergic agents: an autoradiographic analysis. Journal of Clinical Psychiatry 48: 19–25, 1987PubMedGoogle Scholar
  86. Wilens TE, Biederman J, Baldessarini RJ, McDermott SP, Puopolo PR, et al. Fluoxetine inhibits desipramine metabolism. Archives of General Psychiatry 49: 752, 1992PubMedCrossRefGoogle Scholar
  87. Wright CE, Lasher Sisson TA, Steenwyk RC, Swanson CN. A pharmacokinetic evaluation of the combined administration of triazolam and fluoxetine. Pharmacotherapy 12: 103–106, 1992PubMedGoogle Scholar
  88. Zanger UM, Vilbois F, Hardwick JP, Meyer UA. Absence of hepatic cytochrome P450I causes genetically deficient debrisoquine oxidation in man. Biochemistry 27: 5447–5454, 1988PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1994

Authors and Affiliations

  • Alfredo C. Altamura
    • 1
  • Anna R. Moro
    • 2
  • Mauro Percudani
    • 3
  1. 1.Department of PsychiatryUniversity of CagliariCagliariItaly
  2. 2.Department of PsychiatryUniversity of MilanMilanItaly
  3. 3.Department of PsychiatryGeneral Hospital of MagentaMilanItaly

Personalised recommendations