Nordoxepin

Nordoxepin
Clinical data
Other namesN-Desmethyldoxepin; Desmethyldoxepin; Demethyldoxepin; Monodesmethyldoxepin
Pharmacokinetic data
Elimination half-life31 hours[1]
Identifiers
  • (E/Z)-3-(Dibenzo[b,e]oxepin-11(6H)-ylidene)-N-methylpropan-1-amine
CAS Number
PubChem CID
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 as N-desmethyldoxepin, is an organic compound. A colorless solid, it attracted attention as the major active metabolite of the tricyclic antidepressant (TCA) doxepin (Sinequan).[2] It has been found to play a significant role in the antidepressant effects of doxepin.[3]

Nordoxepin is a mixture of (E) and (Z) stereoisomers.[2] Whereas pharmaceutical 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 to stereoselective metabolism of doxepin by cytochrome P450 enzymes, are approximately 1:1.[2]

Nordoxepin is pharmacologically active similarly to doxepin,[4] but relative to doxepin, is much more potent and selective as a norepinephrine reuptake inhibitor.[2][5][6] In general, the demethylated variants of tertiary amine TCAs like doxepin are much more potent inhibitors of norepinephrine reuptake, less potent inhibitors of serotonin reuptake, and less potent in their antiadrenergic, antihistamine, and anticholinergic activities.[5][6][7]

Nordoxepin is formed from doxepin mainly by CYP2C19 (>50% contribution), while CYP1A2 and CYP2C9 are involved to a lesser extent, and CYP2D6 and CYP3A4 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 CYP2D6 ultra-rapid versus poor metabolizers.[3] Both doxepin and nordoxepin are also transformed into glucuronide conjugates.[3] The elimination half-life of nordoxepin is approximately 31 hours, which is almost twice that of doxepin (mean 17 hours).[1]

  1. ^ a b "Sinepin Capsules 25mg - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Marlborough Pharmaceuticals Ltd. 22 September 2011. Retrieved 3 December 2013.
  2. ^ a b c d Williams 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. ^ a b c d Kirchheiner 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. ^ a b 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. ^ a b 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.