Clinical Pharmacokinetics

, Volume 39, Issue 6, pp 413–427 | Cite as

Clinical Pharmacokinetics of Reboxetine, a Selective Norepinephrine Reuptake Inhibitor for the Treatment of Patients with Depression

Review Articles Drug Disposition


Reboxetine is a novel selective norepinephrine inhibitor that has been evaluated in the treatment of patients with depression.

Reboxetine is a racemic mixture, and the (S,S)-(+)-enantiomer appears to be the more potent inhibitor. However, the ratio of the areas under the concentration-time curves of the (S,S)-(+)- and (R,R)-(−)-enantiomers in vivo is approximately 0.5. There is no evidence for chiral inversion. Differences in the clearances of the 2 enantiomers may be explained by differences in protein binding.

The pharmacokinetics of reboxetine are linear following both single and multiple oral doses up to a dosage of 12 mg/day. The plasma concentration-time profile following oral administration is best described by a 1-compartment model, and the mean half-life (approximately 12 hours) is consistent with the recommendation to administer the drug twice daily.

Reboxetine is well absorbed after oral administration. The absolute bioavailability is 94.5%, and maximal concentrations are generally achieved within 2 to 4 hours. Food affects the rate, but not the extent, of absorption. The distribution of reboxetine appears to be limited to a fraction of the total body water due to its extensive (>97%) binding to plasma proteins.

The primary route of reboxetine elimination appears to be through hepatic metabolism. Less than 10% of the dose is cleared renally. Anumber of metabolites formed through hepatic oxidation have been identified, but reboxetine is the major circulating species in plasma. In vitro studies show that reboxetine is predominantly metabolised by cytochrome P450 (CYP) 3A4; CYP2D6 is not involved.

Reboxetine plasma concentrations are increased in elderly individuals and in those with hepatic or renal dysfunction, probably because of reduced metabolic clearance. In these populations, reboxetine should be used with caution, and a dosage reduction is indicated.

Ketoconazole decreases the clearance of reboxetine, so that the dosage of reboxetine may need to be reduced when potent inhibitors of CYP3A4 are coadministered. Quinidine does not affect the in vivo clearance of reboxetine, confirming the lack of involvement of CYP2D6. There is no pharmacokinetic interaction between reboxetine and lorazepam or fluoxetine. Reboxetine at therapeutic concentrations has no effect on the in vitro activity of CYP1A2, 2C9, 2D6, 2E1 or 3A4. The lack of effect of reboxetine on CYP2D6 and CYP3A4 was confirmed by the lack of effect on the metabolism of dextromethorphan and alprazolam in healthy volunteers. Thus, reboxetine is not likely to affect the clearance of other drugs metabolised by CYP isozymes.


  1. 1.
    Melloni P, Carniel G, Delia Toree A, et al. Potential antidepressant agents: α-aryloxy-benzyl derivatives of ethanolamine and morpholine. Eur J Med Chem Chim Thér 1984; 19: 235–42.Google Scholar
  2. 2.
    Gorman JM, Nemeroff CB, chairs. The role of norepinephrine in the treatment of depression [academic highlights]. J Clin Psychiatry 1999 Sep; 60 (9): 623–31.CrossRefGoogle Scholar
  3. 3.
    Riva M, Brunello N, Rovescalli AC, et al. Effect of reboxetine, a new antidepressant drug, on the central noradrenergic system: behavioural and biochemical studies. J Drug Dev 1989; 1: 243–53.Google Scholar
  4. 4.
    Versiani M, Mehilane L, Gaszner P, et al. Reboxetine, a unique selective NRI, prevents relapse and recurrence in long-term treatment of major depressive disorder. J Clin Psychiatry 1999 Jun; 60 (6): 400–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Massana J, Moller HJ, Burrows GD, et al. Reboxetine: a double-blind comparison with fluoxetine in major depressive disorder. Int Clin Psychopharmacol 1999 Mar; 14 (2): 73–80.PubMedCrossRefGoogle Scholar
  6. 6.
    Dostert P, Benedetti MS, Poggesi I. Review of the pharmacokinetics and metabolism of reboxetine, a selective noradrenaline reuptake inhibitor. Eur Neuropsychopharmacol 1997; 7 Suppl. 1: S23–35.PubMedCrossRefGoogle Scholar
  7. 7.
    DeVane CL. Differential pharmacology of the newer antidepressants. J Clin Psychiatry 1998; 59 Suppl. 20: 85–93.PubMedGoogle Scholar
  8. 8.
    Caccia S. Metabolism of the newer antidepressants: an overview of the pharmacological and pharmacokinetic implications. Clin Pharmacokinet 1998 Apr; 34 (4): 281–302.PubMedCrossRefGoogle Scholar
  9. 9.
    Strolin-Benedetti M, Frigerio E, Tocchetti P, et al. Stereoselective and species-dependent kinetics of reboxetine in mouse and rat. Chirality 1995; 7 (4): 285–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Denolle T, Pellizzoni C, Jannuzzo MG, et al. Hemodynamic effects of reboxetine in healthy male volunteers. Clin Pharmacol Ther 1999 Sep; 66 (3): 282–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Fleishaker JC, Mucci M, Pellizzoni C, et al. Absolute bioavailability of reboxetine enantiomers and effect of gender on pharmacokinetics. Biopharm Drug Dispos 1999 Jan; 20 (1): 53–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Edwards DM, Pellizzoni C, Breuel HP, et al. Pharmacokinetics of reboxetine in healthy volunteers. Single oral doses, linearity and plasma protein binding. Biopharm Drug Dispos 1995 Aug; 16 (6): 443–60.PubMedCrossRefGoogle Scholar
  13. 13.
    Pellizzoni C, Strolin Benedetti M, Poggesi I, et al. Pharmacokinetics of reboxetine in healthy volunteers: relative bioavailability and food effect [abstract]. Pharmacol Res 1995; 31 Suppl.: 41.CrossRefGoogle Scholar
  14. 14.
    Jannuzzo MG, Ryde M, Karlmark B, et al. Pharmacokinetics of reboxetine in healthy volunteers of different ages. Eur Neuropsychopharmacol 1995; 5: 300.Google Scholar
  15. 15.
    Jannuzzo MG, Strolin Benedetti M, Duchene P, et al. Pharmacokinetics of reboxetine in the elderly: advances in simultaneous pharmacokinetic/pharmacodynamic modeling [abstract]. 2nd International Symposium: Measurement and Kinetics of In Vivo Drug Effects; 1994 Apr 14–16; Noorwijkerhout (The Netherlands): 94–6.Google Scholar
  16. 16.
    Coulomb F, Ducret F, Fiorentini F, et al. Pharmacokinetics of single-dose reboxetine in volunteers with renal insufficiency. J Clin Pharmacol 2000; 40: 482–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Tran A, Laneury JP, Duchêne P, et al. Pharmacokinetics of reboxetine in volunteers with hepatic impairment. Clin Drug Invest 2000; 19 (6): 473–7.CrossRefGoogle Scholar
  18. 18.
    Fiorentini F, Poggesi I, Januzzo MG, et al. Effect of lorazepam on the pharmacokinetics of reboxetine in healthy volunteers [abstract]. Eur Neuropsychopharmacol 1995; 5: 300.CrossRefGoogle Scholar
  19. 19.
    Rocchetti M, Pellizzoni C, Poggesi I, et al. Genetic polymorphism and reboxetine metabolism [abstract 80]. 1st Congress of the European Association for Clinical Pharmacology and Therapeutics; 1995 Sep 27; Paris. Therapie 1995; 50 Suppl.Google Scholar
  20. 20.
    Rey E, Dostert P, d’Athis Ph, et al. Dose proportionality of reboxetine enantiomers in healthy volunteers. Biopharm Drug Dispos 1999 May; 20 (4): 177–81.PubMedCrossRefGoogle Scholar
  21. 21.
    Herman BD, Fleishaker JC, Brown MT. Ketoconazole inhibits the clearance of the enantiomers of the antidepressant reboxetine in humans. Clin Pharmacol Ther 1999 Oct; 66 (4): 374–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Pellizzoni C, Poggesi I, Jørgensen NP, et al. Pharmacokinetics of reboxetine in healthy volunteers: single against repeated oral doses and lack of enzymatic alterations. Biopharm Drug Dispos 1996 Oct; 17 (7): 623–33.PubMedCrossRefGoogle Scholar
  23. 23.
    Fleishaker JC, Francom SF, Herman BD, et al. Lack of effect of reboxetine on electrocardiographic parameters in healthy volunteers [abstract]. Clin Pharmacol Ther 2000 Feb; 67 (2): 109.Google Scholar
  24. 24.
    Cocchiara G, Battaglia R, Pevarello P, et al. Comparison of the disposition and of the metabolic pattern of reboxetine, a new antidepressant, in the rat, dog, monkey and man. Eur J Drug Metab Pharmacokinet 1991 Jul–Sep; 16 (3): 231–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Fleishaker JC, Herman BD, Pearson LK, et al. Evaluation of the potential pharmacokinetic/pharmacodynamic interaction between fluoxetine and reboxetine in healthy volunteers. Clin Drug Invest 1999 Aug; 18 (2): 141–50.CrossRefGoogle Scholar
  26. 26.
    Destination and fate of 14C-FLE20124 administered orally to healthy volunteers. Data on file, Pharmacia & Upjohn, Inc., Nerviano, Italy, 1985.Google Scholar
  27. 27.
    Wienkers LC, Allievi C, Hauer MJ, et al. Cytochrome P450-mediated metabolism of the individual enantiomers of the antidepressant agent reboxetine in human liver microsomes. Drug Metab Dispos 1999 Nov; 27 (11): 1334–40.PubMedGoogle Scholar
  28. 28.
    Strolin-Benedetti M, Pellizzoni C, Pogessi I, et al. Pharmacokinetics of reboxetine enantiomers in healthy volunteers. Can J Physiol Pharmacol 1994; 72 Suppl. 1: P13.21.17.Google Scholar
  29. 29.
    Poggesi I, Pellizzoni C, Fleishaker JC. Pharmacokinetics of reboxetine in elderly patients with depressive disorders. Int J Clin Pharmacol Ther 2000; 38: 254–9.PubMedGoogle Scholar
  30. 30.
    Yuan R, Venitz J. Chronic renal failure (CRF) affects the disposition of hepatically metabolized drugs. Pharm Sci 1999; 1 (4 Suppl.).Google Scholar
  31. 31.
    Schmith VD, Piraino B, Smith RB, et al. Alprazolam in end-stage renal disease: I. Pharmacokinetics. J Clin Pharmacol 1991; 31: 571–9.PubMedGoogle Scholar
  32. 32.
    Davies DS, Murray S, Edwards RJ, et al. Inhibitory potential of reboxetine on major drug metabolizing forms of P450 in humans [abstract]. American College of Neuropsychopharmacology 36th Annual Meeting; 1997 Dec 8–12; Waikoloa (HI).Google Scholar
  33. 33.
    Januzzo MG, Bosc M, Renoux A, et al. Effect of reboxetine on the pharmacokinetics of lorazepam in healthy volunteers [abstract]. Eur Neuropsychopharmacol 1995; 5: 300–1.Google Scholar
  34. 34.
    White K, Simpson G. Combined MAOI-tricyclic antidepressant treatment: a reevaluation. J Clin Psychopharmacol 1981; 1: 264–82.PubMedCrossRefGoogle Scholar
  35. 35.
    Feighner JP, Boyer WF, Tyler DL, et al. Adverse consequences of fluoxetine-MAOi combination therapy. J Clin Psychiatr 1990; 51: 222–5.Google Scholar
  36. 36.
    Sternbach H. The serotonin syndrome. J Clin Psychopharmacol 1991; 11: 277–9.CrossRefGoogle Scholar
  37. 37.
    Greenblatt DJ, von Moltke LL, Schmider J, et al. Inhibition of human cytochrome P450-3A isoforms by fluoxetine and norfluoxetine: in vitro and in vivo studies. J Clin Pharmacol 1996; 36: 792–8.PubMedGoogle Scholar
  38. 38.
    Avenoso A, Facciolà G, Scordo MG, et al. No effect of the new antidepressant reboxetine on CYP2D6 activity in healthy volunteers. Ther Drug Monit 1999 Oct; 21 (5): 577–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Lam Y, Ereshefsky L, Toney G, et al. The effects of reboxetine and nefazodone on the pharmacokinetics and pharmacodynamics of alprazolam. Annual Meeting of the American Psychiatric Association; 2000 May 13–18; Chicago (IL).Google Scholar

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  1. 1.Clinical Pharmacology Unit, 7215-24-205Pharmacia & Upjohn, Inc.KalamazooUSA

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