Reboxetine

Reboxetine
Systematic (IUPAC) name
(R*,R*)-2-[(2-ethoxyphenoxy)-phenyl-methyl]morpholine
Clinical data
Pregnancy cat.  ?
Legal status Prescription only
Routes Oral
Pharmacokinetic data
Bioavailability 94.5%[1]
Protein binding 98%
Metabolism Hepatic, CYP3A4-mediated
Half-life 13 hours[2]
Excretion Renal
Identifiers
CAS number 98769-81-4 YesY
ATC code N06AX18
PubChem CID 127151
DrugBank DB00234
ChemSpider 112870 YesY
UNII 947S0YZ36I N
KEGG D08472 YesY
ChEMBL CHEMBL14370 N
Chemical data
Formula C19H23NO3 
Mol. mass 313.391 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Reboxetine is a drug marketed as an antidepressant for use in the treatment of clinical depression, panic disorder and ADD/ADHD, developed by Pharmacia (now Pfizer). Its mesylate (i.e. methanesulfonate) salt is sold under tradenames including Edronax, Norebox, Prolift, Solvex, Davedax or Vestra. It is approved for use in many European countries, but has not been approved for use in the United States because of a lack of proven efficacy.

According to a meta-analysis of 12 new-generation antidepressants, reboxetine was no more effective than placebo, was "significantly less" effective, and was less acceptable, than the other drugs in treating the acute-phase treatment of adults with unipolar major depression.[3][4][5]

According to a systematic review and meta-analysis by IQWiG, including unpublished data, published data on reboxetine overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also underestimated harm, concluding that reboxetine was an ineffective and potentially harmful antidepressant. The study also showed that nearly three quarters of the data on patients who took part in trials of reboxetine were not published by Pfizer until now.[6]

Reboxetine has two chiral centers. Thus, four stereoisomers may exist, the (R,R)-, (S,S)-, (R,S)-, and (S,R)-isomers. The active ingredient of reboxetine is a racemic mixture of two enantiomers, the (R,R)-(–)- and (S,S)-(+)-isomer.[7]

Contents

Mode of action

Unlike most antidepressants on the market, reboxetine is a norepinephrine reuptake inhibitor (NRI); it does not inhibit the reuptake of serotonin.[8]

Side effects

Common side effects of reboxetine include: dry mouth, constipation, headache, drowsiness, dizziness, excessive sweating and insomnia. Hypertension has been infrequently seen.

In 4 to 8% of all patients treated the medication has to be discontinued due to following reasons (percentages represent mean values):

  • insomnia 1.3%
  • excessive sweating 1.1%
  • vertigo/hypotension and paraesthesia 0.8%
  • dizziness, impotence, and other urological problems 0.5% each

Some other rare side effects include anxiety, loss of appetite, loss of libido, urinary retention in men, pain on ejaculation, increased orgasm intensity, and premature/quickened ejaculation.

Reboxetine is normally well tolerated. So far no attributable fatalities have been noted.

Metabolism

Both the (R,R)-(–) and (S,S)-(+)-enantiomers of reboxetine are predominantly metabolized by the CYP3A4 isoenzyme.[9] The primary metabolite of reboxetine is O-desethylreboxetine, and there are also three minor metabolites—Phenol A, Phenol B, and UK1, Phenol B being the most minor.[9]

Interactions with other medications

Because of its reliance on CYP3A4, reboxetine O-desethylation is markedly inhibited by papaverine and ketoconazole.[9]

According to Weiss et al., reboxetine is an intermediate-level inhibitor of P-glycoprotein, which gives it the potential to interact with ciclosporin, tacrolimus, paroxetine, sertraline, quinidine, fluoxetine, fluvoxamine.[10]

The potency and duration of the effects of benzodiazepines can be increased because reboxetine interferes with their excretion.

History

By mid-2007, reboxetine was licensed worldwide in over 50 countries, including Italy, Germany and the United Kingdom. In May 2007, however, the Food and Drug Administration declined Pharmacia's license application for the American market. Therefore it is yet to be available in the United States.

Chemistry

Reboxetine synth.png

[11]

Notes and references

  1. ^ Fleishaker JC (2000). "Clinical pharmacokinetics of reboxetine, a selective norepinephrine reuptake inhibitor for the treatment of patients with depression". Clinical Pharmacokinetics 39 (6): 413–27. doi:10.2165/00003088-200039060-00003. PMID 11192474. 
  2. ^ Edwards DM, Pellizzoni C, Breuel HP, Berardi A, Castelli MG, Frigerio E, Poggesi I, Rocchetti M, Dubini A, Strolin Benedetti M (1995). "Pharmacokinetics of reboxetine in healthy volunteers. Single oral doses, linearity and plasma protein binding". Biopharmaceutics & Drug Disposition 16 (6): 443–60. doi:10.1002/bdd.2510160603. PMID 7579027. 
  3. ^ Analysis shows sertraline and escitalopram are the best of 12 new-generation antidepressants Lancet Public release date: 28-Jan-2009
  4. ^ Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis, Andrea Cipriani, Toshiaki A Furukawa, Georgia Salanti, John R Geddes, et al. The Lancet, Published Online, January 29, 2009, DOI:10.1016/S0140-6736(09)60046-5
  5. ^ Zoloft, Lexapro the Best of Newer Antidepressants, HealthDay News, Washington Post, January 29, 2009
  6. ^ Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials British Medical Journal Public release date: 12-Oct-2010
  7. ^ Melloni P, Della Torre A, Lazzari E, Mazzini G and Meroni M (1985). "Configuration studies on 2-[alpha -(2-ethoxyphenoxy)benzyl]-morpholine FCE 20124". Tetrahedron 41 (1): 1393–1399. doi:10.1016/S0040-4020(01)96541-X. 
  8. ^ Kent JM. (2000). "SNaRIs, NaSSAs, and NaRIs: new agents for the treatment of depression". The Lancet 355 (9207): 911–918. doi:10.1016/S0140-6736(99)11381-3. PMID 10752718. 
  9. ^ a b c Wienkers LC, Allievi C, Hauer MJ, Wynalda MA. (1999). "Cytochrome P-450-Mediated Metabolism of the Individual Enantiomers of the Antidepressant Agent Reboxetine in Human Liver Microsomes". Drug Metabolism & Disposition 27 (11): 1334–1340. PMID 10534319. 
  10. ^ Weiss J, Dormann SM, Martin-Facklam M, Kerpen CJ, Ketabi-Kiyanvash N, Haefeli WE (2003). "Inhibition of P-glycoprotein by newer antidepressants". Journal of Pharmacology & Experimental Therapeutics 305 (1): 197–204. doi:10.1124/jpet.102.046532. PMID 12649369. 
  11. ^ Brenner, Eric; Baldwin, Ronald M.; Tamagnan, Gilles (2005). "Asymmetric Synthesis of (+)-(S,S)-Reboxetine via a New (S)-2-(Hydroxymethyl)morpholine Preparation". Organic Letters 7 (5): 937–9. doi:10.1021/ol050059g. PMID 15727479. 

External links


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