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Nordoxepin

From Wikipedia, the free encyclopedia
Active metabolite of antidepressant drug doxepin
Pharmaceutical compound
Nordoxepin
Clinical data
Other namesN-Desmethyldoxepin; Desmethyldoxepin; Demethyldoxepin; Monodesmethyldoxepin
Pharmacokinetic data
Eliminationhalf-life31 hours[1]
Identifiers
  • (E/Z)-3-(Dibenzo[b,e]oxepin-11(6H)-ylidene)-N-methylpropan-1-amine
CAS Number
PubChemCID
ChemSpider
UNII
ChEBI
CompTox Dashboard(EPA)
Chemical and physical data
FormulaC18H19NO
Molar mass265.356 g·mol−1
3D model (JSmol)
  • CNCCC=C1C2=CC=CC=C2COC3=CC=CC=C31
  • InChI=1S/C18H19NO/c1-19-12-6-10-16-15-8-3-2-7-14(15)13-20-18-11-5-4-9-17(16)18/h2-5,7-11,19H,6,12-13H2,1H3
  • Key:HVKCEFHNSNZIHO-UHFFFAOYSA-N

Nordoxepin, also known asN-desmethyldoxepin, is anorganic compound. A colorless solid, it attracted attention as the majoractive metabolite of thetricyclic antidepressant (TCA)doxepin (Sinequan).[2] It has been found to play a significant role in theantidepressant effects of doxepin.[3]

Nordoxepin is amixture of(E) and (Z)stereoisomers.[2] Whereaspharmaceutical doxepin is supplied in an approximate 85:15 ratio mixture of (E)- and (Z)-stereoisomers and plasma concentrations of doxepin remain roughly the same as this ratio with treatment, plasma levels of the (E)- and (Z)-stereoisomers of nordoxepin, due tostereoselectivemetabolism of doxepin bycytochrome P450enzymes, are approximately 1:1.[2]

Nordoxepin ispharmacologically active similarly to doxepin.[4] In general, the demethylated variants oftertiary amine TCAs like doxepin are much more potentnorepinephrine reuptake inhibitors, less potentserotonin reuptake inhibitors, and less potent in theirantiadrenergic,antihistamine, andanticholinergic activities.[5][6][7]

Nordoxepin is formed from doxepin mainly byCYP2C19 (>50% contribution), whileCYP1A2 andCYP2C9 are involved to a lesser extent, andCYP2D6 andCYP3A4 are not involved.[8]Hydroxylation of doxepin and nordoxepin is mediated mainly by CYP2D6.[3] Total exposures to both doxepin and nordoxepin differ by almost 10-fold in CYP2D6ultra-rapid versuspoor metabolizers.[3] Both doxepin and nordoxepin are alsotransformed intoglucuronideconjugates.[3] Theelimination half-life of nordoxepin is approximately 31 hours, which is almost twice that of doxepin (mean 17 hours).[1]

See also

[edit]

References

[edit]
  1. ^ab"Sinepin Capsules 25mg - Summary of Product Characteristics (SPC)".electronic Medicines Compendium. Marlborough Pharmaceuticals Ltd. 22 September 2011. Retrieved3 December 2013.
  2. ^abcWilliams DA (24 January 2012)."Antidepressant". In Lemke TL, Williams DA (eds.).Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 605–.ISBN 978-1-60913-345-0.
  3. ^abcdKirchheiner J, Henckel HB, Franke L, Meineke I, Tzvetkov M, Uebelhack R, et al. (August 2005). "Impact of the CYP2D6 ultra-rapid metabolizer genotype on doxepin pharmacokinetics and serotonin in platelets".Pharmacogenetics and Genomics.15 (8):579–587.doi:10.1097/01.fpc.0000167331.30905.9e.PMID 16007002.S2CID 41765748.
  4. ^Weber J, Siddiqui MA, Wagstaff AJ, McCormack PL (August 2010). "Low-dose doxepin: in the treatment of insomnia".CNS Drugs.24 (8):713–720.doi:10.2165/11200810-000000000-00000.PMID 20658801.S2CID 26739281.
  5. ^Dawkins K, Manji HK, Potter WZ (20 September 1994)."Pharmacodynamics of Antidepressants". In Cutler NR, Sramek JJ, Narang PK (eds.).Pharmacodynamics and Drug Development: Perspectives in Clinical Pharmacology. John Wiley & Sons. pp. 160–.ISBN 978-0-471-95052-3.
  6. ^Baumann P, Hiemke C (23 February 2012)."Central Nervous System Drugs". In Anzenbacher P, Zanger UM (eds.).Metabolism of Drugs and Other Xenobiotics. John Wiley & Sons. pp. 302–.ISBN 978-3-527-64632-6.
  7. ^Nelson JG (2009)."Tricyclic and Tetracyclic Drugs". In Schatzberg AF, Nemeroff CB (eds.).The American Psychiatric Publishing Textbook of Psychopharmacology. American Psychiatric Pub. pp. 264–.ISBN 978-1-58562-309-9.
  8. ^Härtter S, Tybring G, Friedberg T, Weigmann H, Hiemke C (July 2002). "The N-demethylation of the doxepin isomers is mainly catalyzed by the polymorphic CYP2C19".Pharmaceutical Research.19 (7):1034–1037.doi:10.1023/a:1016478708902.PMID 12180536.S2CID 8089917.
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