Etoposide

Etoposide
Names
Pronunciation/ˌɛtoʊˈpoʊsaɪd/
Trade namesEtopophos, Toposar, others
Other namesVP-16; VP-16-213
IUPAC name
  • 4'-Demethyl-epipodophyllotoxin 9-[4,6-O-(R)-ethylidene-beta-D-glucopyranoside], 4' -(dihydrogen phosphate)
Clinical data
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
    Routes of
    use    		by mouth, intravenous
    Defined daily dosenot established[1]
    External links
    AHFS/Drugs.comMonograph
    US NLMEtoposide
    MedlinePlusa684055
    Legal
    Legal status
    Pharmacokinetics
    BioavailabilityHighly variable, 25 to 75%
    Protein binding97%
    MetabolismLiver (CYP3A4 involved)
    Elimination half-lifeOral: 6 h., IV: 6-12 h., IV in children: 3 h.
    ExcretionKidney and fecal
    Chemical and physical data
    FormulaC29H32O13
    Molar mass588.562 g·mol−1
    3D model (JSmol)
    Melting point243.5 °C (470.3 °F)
    SMILES
    • C[C@@H]1OC[C@@H]2[C@@H](O1)[C@@H]([C@H]([C@@H](O2)O[C@@H]3c4cc5c(cc4[C@H]([C@@H]6[C@@H]3COC6=O)c7cc(c(c(c7)OC)O)OC)OCO5)O)O
    InChI
    • InChI=1S/C29H32O13/c1-11-36-9-20-27(40-11)24(31)25(32)29(41-20)42-26-14-7-17-16(38-10-39-17)6-13(14)21(22-15(26)8-37-28(22)33)12-4-18(34-2)23(30)19(5-12)35-3/h4-7,11,15,20-22,24-27,29-32H,8-10H2,1-3H3/t11-,15+,20-,21-,22+,24-,25-,26-,27-,29+/m1/s1 checkY
    • Key:VJJPUSNTGOMMGY-MRVIYFEKSA-N checkY

    Etoposide, sold under the brand name Etopophos among others, is a chemotherapy medication used for the treatments of a number of types of cancer including testicular cancer, lung cancer, lymphoma, leukemia, neuroblastoma, and ovarian cancer.[2] It is also used for hemophagocytic lymphohistiocytosis.[3] It is used by mouth or injection into a vein.[2]

    Side effects are very common.[2] They can include low blood cell counts, vomiting, loss of appetite, diarrhea, hair loss, and fever.[2] Other severe side effects include allergic reactions and low blood pressure.[2][4] Use during pregnancy will likely harm the baby.[2] Etoposide is in the topoisomerase inhibitor family of medication.[2] It is believed to work by damaging DNA.[2]

    Etoposide was approved for medical use in the United States in 1983.[2] It is on the World Health Organization's List of Essential Medicines.[5] The wholesale cost in the developing world is about US$3.24 to US$5.18 per 100 mg vial.[6] In the United Kingdom this costs the NHS about £12.15 as of 2015.[7]

    Medical uses

    Etoposide is used as a form of chemotherapy for cancers such as Kaposi’s sarcoma, Ewing's sarcoma, lung cancer, testicular cancer, lymphoma, nonlymphocytic leukemia, and glioblastoma multiforme. It is often given in combination with other drugs (such as bleomycin in treating testicular cancer). It is also sometimes used in a conditioning regimen prior to a bone marrow or blood stem cell transplant.[8]

    Administration

    It is given intravenously (IV) or orally in capsule or tablet form. If the drug is given IV, it must be done slowly over a 30- to 60-minute period because it can lower blood pressure as it is being administered. Blood pressure is checked often during infusing, with the speed of administration adjusted accordingly.

    Dosage

    The defined daily dose is not established[1]

    Side effects

    Common are:

    Less common are:

    When given with warfarin, it may cause bleeding.[9]

    Pharmacology

    Mechanism of action

    Etoposide forms a ternary complex with DNA and the topoisomerase II enzyme (which aids in relaxing negative or positive supercoils in DNA), prevents re-ligation of the DNA strands, and by doing so causes DNA strands to break.[10] Cancer cells rely on this enzyme more than healthy cells, since they divide more rapidly. Therefore, this causes errors in DNA synthesis and promotes apoptosis of the cancer cell.[8][11]

    Chemistry

    An illustration of the wild mandrake, showing part of the rhizome (at bottom)

    Etoposide is a semisynthetic derivative of podophyllotoxin from the rhizome of the wild mandrake (Podophyllum peltatum). More specifically, it is a glycoside of podophyllotoxin with a D-glucose derivative. It is chemically similar to the anti-cancer drug teniposide, being distinguished only by a methyl group where teniposide has a thienyl.[12] Both these compounds have been developed with the aim of creating less toxic derivatives of podophyllotoxin.[13]

    The substance is a white to yellow-brown, crystalline powder. It is soluble in organic solvents.[13]

    It is used in form of its salt etoposide phosphate.

    History

    Etoposide was first synthesized in 1966 and U.S. Food and Drug Administration approval was granted in 1983.[8]

    The nickname VP-16 likely comes from a compounding of the last name of one of the chemists who performed early work on the drug (von Wartburg) and podophyllotoxin.[14] Another scientist who was integral in the development of podophyllotoxin-based chemotherapeutics was the medical pharmacologist Hartmann F. Stähelin.

    References

    1. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 31 July 2020. Retrieved 18 September 2020.
    2. 1 2 3 4 5 6 7 8 9 "Etoposide". The American Society of Health-System Pharmacists. Archived from the original on 31 March 2016. Retrieved 8 December 2016.
    3. ↑ Yildiz, H.; Van Den Neste, E.; Defour, J. P.; Danse, E.; Yombi, J. C. (2020). "Adult haemophagocytic lymphohistiocytosis: A Review". QJM : Monthly Journal of the Association of Physicians. doi:10.1093/qjmed/hcaa011. PMID 31943120.
    4. ↑ World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. p. 227. hdl:10665/44053. ISBN 9789241547659.
    5. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
    6. ↑ "Etoposide". International Drug Price Indicator Guide. Archived from the original on 8 July 2018. Retrieved 8 December 2016.
    7. ↑ British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 593. ISBN 9780857111562.
    8. 1 2 3 Hande KR (1998). "Etoposide: four decades of development of a topoisomerase II inhibitor". Eur. J. Cancer. 34 (10): 1514–21. doi:10.1016/S0959-8049(98)00228-7. PMID 9893622.
    9. ↑ Longe JL (2002). Gale Encyclopedia Of Cancer: A Guide To Cancer And Its Treatments. Detroit: Thomson Gale. pp. 397–399. ISBN 978-1-4144-0362-5.
    10. ↑ Pommier Y, Leo E, Zhang H, Marchand C (2010). "DNA topoisomerases and their poisoning by anticancer and antibacterial drugs". Chem. Biol. 17 (5): 421–33. doi:10.1016/j.chembiol.2010.04.012. PMID 20534341.
    11. ↑ Gordaliza M, García PA, del Corral JM, Castro MA, Gómez-Zurita MA (2004). "Podophyllotoxin: distribution, sources, applications and new cytotoxic derivatives". Toxicon. 44 (4): 441–59. doi:10.1016/j.toxicon.2004.05.008. PMID 15302526.
    12. ↑ Mutschler, Ernst; Schäfer-Korting, Monika (2001). Arzneimittelwirkungen (in German) (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. pp. 894–5. ISBN 3-8047-1763-2.{{cite book}}: CS1 maint: unrecognized language (link)
    13. 1 2 Dinnendahl, V; Fricke, U, eds. (2015). Arzneistoff-Profile (in German). Vol. 4 (28 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.{{cite book}}: CS1 maint: unrecognized language (link)
    14. ↑ Kuhn M, Von Wartburg A (1967). "Podophyllum-Lignane: Struktur und Absolutkonfiguration von Podorhizol-β-D-glucosid ( = Lignan F). 19. Mitt. über mitosehemmende Naturstoffe [1]". Helvetica Chimica Acta. 50 (6): 1546–65. doi:10.1002/hlca.19670500614. Archived from the original on 2013-01-05.
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