Tamoxifen

from Wikipedia, the free encyclopedia
Structural formula
Structural formula of tamoxifen
General
Non-proprietary name Tamoxifen
other names

( Z ) -2- [4- (1,2-Diphenylbut-1-enyl) phenoxy] - N , N -dimethylethylamine ( IUPAC )

Molecular formula
  • C 26 H 29 NO (tamoxifen)
  • C 26 H 29 NO C 6 H 8 O 7 (tamoxifen citrate)
Brief description

white to almost white, crystalline, polymorphic powder (as dihydrogen citrate)

External identifiers / databases
CAS number
  • 10540-29-1 (tamoxifen)
  • 54965-24-1 (tamoxifen citrate )
EC number 234-118-0
ECHA InfoCard 100.031.004
PubChem 2733526
ChemSpider 2015 313
DrugBank DB00675
Wikidata Q412178
Drug information
ATC code

L02 BA01

Drug class

Selective estrogen receptor modulator

Mechanism of action

competitive inhibition of estrogen receptors

properties
Molar mass
Melting point
  • 97 ° C (tamoxifen)
  • 140–142 ° C (tamoxifen · citrate)
solubility

Water: 0.167 mg l −1 (25 ° C)

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
08 - Dangerous to health

danger

H and P phrases H: 350-360-362
P: 201-263-308 + 313
Toxicological data

4100 mg kg −1 ( LD 50ratoral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Tamoxifen is a selective estrogen receptor modulator that is used as a drug in the treatment of breast cancer in pre- menopausal women . Tamoxifen was developed by ICI Pharmaceuticals (now AstraZeneca ) and causes competitive inhibition of estrogen receptors and stimulation of progesterone receptors .

Clinical information

Application areas (indications)

Tamoxifen is approved for adjuvant therapy after primary treatment of breast cancer and for the treatment of metastatic breast cancer. In the USA, it is also approved for the prevention of breast cancer in high-risk patients. V. Craig Jordan is considered the "father" of breast cancer treatment with tamoxifen in the 1970s.

Tamoxifen has also been used to treat fibrocystic breasts in women to reduce lumps, swelling and pain.

Beyond the drug approval, efficacy in mania has also been observed in a pilot study.

Researchers at the University of San Diego are said to have found out in 2018 that tamoxifen is said to work against the amoeba Naegleria fowleri . In humans, this triggers primary amoebic meningoencephalitis, which is fatal in up to 95% of cases .

Contraindications (contraindications)

Apart from known hypersensitivity, tamoxifen is also contraindicated in children, pregnant women and breastfeeding .

Interactions

As a hormone receptor modulator, tamoxifen has the potential to affect the effects of other hormone preparations. In particular, when estrogens are taken at the same time as tamoxifen, a mutual weakening of the effects can be observed. The effect of the aromatase inhibitor letrozole is also weakened when taken at the same time.

Tamoxifen influences the effects of antiplatelet agents and anticoagulants .

Tamoxifen is the enzyme system cytochrome P450 , in particular the isozymes CYP3A4 and CYP2D6 , metabolized . Since the metabolism to the active metabolite endoxifen is catalyzed by CYP2D6, inhibitors of CYP2D6, in particular numerous antidepressants from the group of selective serotonin reuptake inhibitors , such as paroxetine and fluoxetine , as well as quinidine , cinacalcet and bupropion , can lead to the formation of the active metabolite and thus the effectiveness decrease from tamoxifen. On the other hand, inducers of CYP3A4, such as rifampicin , can lower the plasma level of tamoxifen. The clinical relevance of this interaction has not yet been clarified. In addition, tamoxifen and its metabolites are potent inhibitors of the cytochrome P450 enzyme system.

Side effects

The most common adverse drug effects can be traced back to the effects of Tamoxifen which influence the hormonal system. Hot flashes, menstrual cycle disorders and discharge are very common (> 10%) . Often (1 to 10%) endometrial changes such as polyps , neoplasias and hyperplasias occur due to the agonistic effect of tamoxifen on the endometrium . The relative risk of the occasionally observed endometrial cancer is increased by a factor of 2 to 4 in women treated with tamoxifen compared to women without tamoxifen treatment. Ovarian cysts and uterine sarcomas are rare (<0.1%).

Thromboembolic complications occur frequently (approx. 1–3%), but rarely (0.1%) have fatal consequences.

Some eye side effects such as cataract , retinopathy , optic neuritis and corneal changes have also been described for tamoxifen . For this reason, a regular (one to two year) ophthalmological check-up is recommended for patients who take tamoxifen.

Hypercalcemia is possible with bone tumors or a diet rich in calcium .

pharmacology

Pharmacodynamics (mode of action)

Tamoxifen binds to the estrogen receptors as a selective estrogen receptor modulator (SERM) . Its active metabolites, such as 4-hydroxytamoxifen and endoxifen, have an even higher affinity for estrogen receptors than tamoxifen . As a partial agonist , tamoxifen has a dual molecular profile of action. On the one hand, due to its partial agonistic effect, it has a weak estrogenic active component. On the other hand, it has an antiestrogenic active component, which is based on a competitive displacement of the body's own full agonist estradiol ( competitive antagonism ). Which of the two active components dominates depends on the tissue in question. In breast tissue, the anti-estrogenic active component is responsible for the anti-tumor effect, since the estrogen receptor type ERα, on which tamoxifen has an antagonistic effect, is located here. A relevant estrogenic effect in the uterus is associated with the occurrence of endometrial cancer as a side effect.

Pharmacokinetics

Tamoxifen is a prodrug that is converted into the active endoxifen in a first reaction by CYP2D6. Due to a naturally occurring polymorphism of the CYP2D6 gene , the speed of this activation step varies from person to person . Patients can benefit from a CYP2D6 genotype determination prior to initiating potential tamoxifen therapy. In the case of slow metabolisers, alternative treatments such as B. the administration of aromatase inhibitors , be changed.

Abuse in Sports

Tamoxifen is misused in competitive sport as a doping agent. Usually it is used to suppress the adverse reaction to some anabolic steroids occurring gynecomastia , the enlargement of the mammary glands , used in men. In addition, tamoxifen leads to an increase in the blood plasma concentration of the hormone testosterone in men , which among other things promotes an increase in muscle mass. This effect is based on a suppression of hormonal feedback mechanisms by inhibiting estrogen receptors in the hypothalamus and in the pituitary gland and leads to an increased formation of regulating hormones which promote the formation of sex hormones. Therefore, in sport, attempts are made improperly with the help of tamoxifen at the end of a prolonged use of anabolic steroids to increase the body's own testosterone production, which is reduced due to the feedback mechanism. Tamoxifen is a banned substance in the since 2005 prohibited list of the World Anti-Doping Agency listed (WADA). Possession of more than 600 mg without a prescription is classified in Germany as a “not small amount” according to the AntiDopG , according to the doping agent quantity regulation .

Trade names

Monopreparations

The commercial preparations contain Tamoxifen Citrate: Ebefen (A), Kessar (D, A, CH) Mandofen (D), Nolvadex (D, A, CH), Tamec (CH), Tamokadin (D) and various generics (D, A , CH).

Individual evidence

  1. European Pharmacopoeia, Deutscher Apotheker Verlag Stuttgart, 6th edition, 2008, ISBN 978-3-7692-3962-1 .
  2. a b Entry on Tamoxifen in the DrugBank of the University of Alberta .
  3. ^ The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals. 14th edition. Merck & Co., Whitehouse Station, NJ, USA, 2006, ISBN 0-911910-00-X , p. 1554.
  4. a b Tamoxifen data sheet from Sigma-Aldrich , accessed on April 23, 2011 ( PDF ).
  5. Entry on Tamoxifen in the ChemIDplus database of the United States National Library of Medicine (NLM) .
  6. a b c d Federal Institute for Drugs and Medical Devices (BfArM): Sample text for specialist information on tamoxifen tablets, film-coated tablets . Retrieved November 14, 2011.
  7. ^ Center for Drug Evaluation and Research: Tamoxifen Information: reducing the incidence of breast cancer in women at high risk . US Food and Drug Administration. 03/08/2005. Archived from the original on June 19, 2007. Retrieved July 3, 2007.
  8. Lois Jovanovic, Genell J. Subak-Sharpe: Hormones. The medical manual for women. (Original edition: Hormones. The Woman's Answerbook. Atheneum, New York 1987) From the American by Margaret Auer, Kabel, Hamburg 1989, ISBN 3-8225-0100-X , p. 386.
  9. JM Bebchuk et al .: A preliminary investigation of a protein kinase C inhibitor in the treatment of acute mania. In: Arch. Gen. Psychiatry. Vol. 57, 2000, PMID 10632242 , pp. 95-97.
  10. Carlos A. Zarate Jr. et al .: Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study. In: Bipolar Disorders . Vol. 9, 2007, pp. 561-570, PMID 17845270 , doi: 10.1111 / j.1399-5618.2007.00530.x .
  11. Cancer drug and antidepressants provide clues for treating brain-eating amoeba infections . In: ScienceDaily . ( sciencedaily.com [accessed September 30, 2018]).
  12. D. Schmidt: Endometrial changes after tamoxifen therapy. In: The Pathologist. Vol. 27, No. 1, 2006, pp. 27-32.
  13. Richard Herrmann: Tamoxifen and the eye. ( Memento of the original from July 30, 2016 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. In: ophta. 3/2009, p. 224. @1@ 2Template: Webachiv / IABot / www.ophta.ch
  14. ^ Y. Shang: Molecular mechanisms of estrogen and SERMs in endometrial carcinogenesis . In: Nat. Rev. Cancer . 6, No. 5, May 2006, pp. 360-368. doi : 10.1038 / nrc1879 . PMID 16633364 .
  15. MP Goetz, SK Knox, VJ Suman et al: The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen . In: Breast Cancer Res. Treat. . 101, No. 1, January 2007, pp. 113-121. doi : 10.1007 / s10549-006-9428-0 . PMID 17115111 .
  16. DJ Handelsman: Clinical review: The rationale for banning human chorionic gonadotropin and estrogen blockers in sport . In: J. Clin. Endocrinol. Metab. . 91, No. 5, May 2006, pp. 1646-1653. doi : 10.1210 / jc.2005-2569 . PMID 16478815 .
  17. The 2010 Prohibited List WORLD ANTI-DOPING CODE Valid 1 January 2010 ( Memento of November 22, 2009 in the Internet Archive ) (PDF; 93 kB).
  18. Ordinance on the determination of the significant amount of doping substances (Doping Substances Ordinance - DmMV) .