Endoxifen

Add links
Source: Wikipedia, the free encyclopedia.
Endoxifen
Clinical data
Trade namesZonalta
Other names4-Hydroxy-N-desmethyltamoxifen; Desmethylhydroxytamoxifen
Routes of
administration		By mouth
Identifiers
  • 4-[1-[4-[2-(methylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol
JSmol)
  • CCC(=C(C1=CC=C(C=C1)O)C2=CC=C(C=C2)OCCNC)C3=CC=CC=C3
  • InChI=1S/C25H27NO2/c1-3-24(19-7-5-4-6-8-19)25(20-9-13-22(27)14-10-20)21-11-15-23(16-12-21)28-18-17-26-2/h4-16,26-27H,3,17-18H2,1-2H3
  • Key:MHJBZVSGOZTKRH-UHFFFAOYSA-N

Endoxifen, also known as 4-hydroxy-N-desmethyltamoxifen, is a nonsteroidal selective estrogen receptor modulator (SERM) of the triphenylethylene group as well as a protein kinase C (PKC) inhibitor. It is under development for the treatment of estrogen receptor-positive breast cancer and for the treatment of mania in bipolar disorder.[1][2] It is taken by mouth.[2]

Endoxifen is an active metabolite of tamoxifen and has been found to be effective in patients that have failed previous hormonal therapies (tamoxifen, aromatase inhibitors, and fulvestrant). [3][4][5] The prodrug tamoxifen is metabolized by the CYP2D6 enzyme to produce endoxifen and afimoxifene (4-hydroxytamoxifen).[6]

Currently, endoxifen is approved by Drugs Controller General of India for the acute treatment of manic episode with or without mixed features of Bipolar I disorder.[7] It is manufactured and sold by Intas Pharmaceuticals under the brand name Zonalta.[8]

Medical uses

Bipolar disorder

Endoxifen is used to treat

mixed episodes associated with bipolar I disorder in India.[9][7] It has been found that the endoxifen improves manic symptoms as well as mixed episode symptoms of patients with bipolar I disorder and has been considered an effective and well-tolerated treatment for this condition.[10]

Clinical Global Impression-Severity of Illness scores.[12]

Side effects

The most prevalent side effects for endoxifen include headache, vomiting, insomnia. Other side effects were: gastritis, epigastric discomfort, diarrhea, restlessness, somnolence, etc.[8] Some of the adverse events reported with other therapies for the management of manic episodes of bipolar I disorder were not observed during the clinical development program of endoxifen like reduction in platelet count, change in blood thyroid-stimulating hormone levels. There were no deaths, serious or significant adverse events during the conduct of trials. Overall, endoxifen was found to be well-tolerated and safe in patients of bipolar I disorder with acute manic episodes with or without mixed features.[12][10] An important caveat here is that the trial was of very short duration (only three weeks). The long-term safety of Endoxifen has not been established among patients with Bipolar Disorder.

Pharmacology

Pharmacodynamics

Selective estrogen receptor modulator

Endoxifen is a

N-desmethyltamoxifen had 2.4%.[15]

Protein kinase C inhibition

The exact mechanism by which endoxifen exerts its therapeutic effects has not been established in bipolar I disorder. However, the efficacy of endoxifen could be mediated through protein kinase C (PKC). The PKC represents a family of enzymes highly enriched in the brain, where it plays a major role in regulating both pre-and post-synaptic aspects of neurotransmission. Excessive activation of PKC results in symptoms related to bipolar disorder. The PKC signaling pathway is a target for the actions of two structurally dissimilar antimanic agents – lithium and valproate.[8]

Endoxifen exhibits 4-fold higher potency in inhibiting PKC activity compared to tamoxifen in preclinical studies and is not dependent on the isozyme cytochrome P450 2D6 (CYP2D6) for action on the target tissues.[16]

Pharmacokinetics

Orally administered endoxifen is rapidly absorbed and systemically available. The time to peak (Tmax) is between 4.5 and 6 hours after oral administration. It is not metabolized by cytochrome P450 enzymes. The half-life (t½) life of endoxifen is 52.1 to 58.1 hours.[17]

Research

Endoxifen has been investigated as a potential drug in the treatment of breast cancer.[18][19]

References

  1. ^ "Z-endoxifen hydrochloride". NCI Drug Dictionary.
  2. ^ a b "Endoxifen - Intas Pharmaceuticals/Jina pharmaceuticals - AdisInsight".
  3. PMID 23382923
    .
  4. PMID 19244106
    .
  5. PMID 24853369
    .
  6. ^ Wilcken N (2016). "Breast cancer: a disease of subtypes". Cancer Forum. 40 (3). Archived from the original on 2016-12-03. Retrieved 2016-11-12.
  7. ^ a b "List of new drugs approved in the year 2019 till date" (PDF). Central Drugs Standard Control Organisation. 1 October 2021. p. 4.
  8. ^ a b c "Drug Fact Sheet - Zonalta" (PDF). Intas Pharmaceuticals. 1 October 2021.
  9. ISBN 978-1-84973-365-6
    .
  10. ^
    PMID 27346789
    .
  11. PMID 19552485
    .
  12. ^
    S2CID 229688331
    .
  13. ^
    S2CID 37932
    .
  14. ^
    PMID 28858267
    .
  15. PMID 25258390
    .
  16. PMID 20227879
    .
  17. S2CID 24590365
    .
  18. ISBN 978-1-4649-6344-5
    .
  19. PMID 29741509
    .

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Endoxifen&oldid=1212668177"