Phytomenadione

Phytomenadione
Names
Trade namesMephyton, others
Other namesVitamin K1, phytonadione, phylloquinone, (E)-phytonadione
IUPAC name
  • 2-methyl-3-[(E,7R,11R)-3,7,11,15-tetramethylhexadec-2-enyl]naphthalene-1,4-dione
Clinical data
Drug classVitamin
Main usesWarfarin overdose, vitamin K deficiency, obstructive jaundice[1]
Side effectsPain at the site of injection, altered taste, allergic reaction[1]
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Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    use    		By mouth, subQ, IM, IV
    Defined daily dose20 mg[2]
    External links
    AHFS/Drugs.comMonograph
    Legal
    Legal status
    Chemical and physical data
    FormulaC31H46
    Molar mass418.709 g·mol−1
    3D model (JSmol)
    SMILES
    • CC1=C(C(=O)c2ccccc2C1=O)C/C=C(\C)/CCC[C@H](C)CCC[C@H](C)CCCC(C)C
    InChI
    • InChI=1S/C31H46O2/c1-22(2)12-9-13-23(3)14-10-15-24(4)16-11-17-25(5)20-21-27-26(6)30(32)28-18-7-8-19-29(28)31(27)33/h7-8,18-20,22-24H,9-17,21H2,1-6H3/b25-20+/t23-,24-/m1/s1 checkY
    • Key:MBWXNTAXLNYFJB-NKFFZRIASA-N

    Phytomenadione, also known as vitamin K1 or phylloquinone, is a vitamin found in food and used as a dietary supplement.[3][1] As a supplement it is used to treat certain bleeding disorders.[1] This includes warfarin overdose, vitamin K deficiency, and obstructive jaundice.[1] It is also recommended to prevent and treat vitamin K deficiency bleeding in infants.[1] Use is typically recommended by mouth or injection under the skin.[1] Use by injection into a vein or muscle is recommended only when other routes are not possible.[1] When given by injection benefits are seen within two hours.[1]

    Common side effects when given by injection include pain at the site of injection and altered taste.[1] Severe allergic reactions may occur when it is injected into a vein or muscle.[1] It is unclear if use during pregnancy is safe; however, use is likely okay during breastfeeding.[4] It works by supplying a required component for making a number of blood clotting factors.[1] Found sources include green vegetables, vegetable oil, and some fruit.[5]

    Phytomenadione was first isolated in 1939.[6] In 1943 Edward Doisy and Henrik Dam were given a Nobel Prize for its discovery.[6] It is on the World Health Organization's List of Essential Medicines.[7] The wholesale cost in the developing world is about 0.11 to 1.27 USD for a 10 mg vial.[8] In the United States a course of treatment costs less than 25 USD.[9]

    Medical uses

    Dosage

    The defined daily dose is 20 milligrams by injection or by mouth.[2] For prevention of bleeding in the newborn it is used at a dose of 0.5 mg by injection for those who weight less than 1.5 kg and 1 mg for those who weight more.[10] For treatment of bleeding in the newborn it is used at a dose of 1 mg three times per day.[10]

    Terminology

    Phytomenadione is often also called phylloquinone, vitamin K,[11] or phytonadione. Sometimes a distinction is made between phylloquinone, which is considered to be a natural substance, and phytonadione, which is considered to be a synthetic substance.[12]

    A stereoisomer of phylloquinone is called vitamin k1 (note the difference in capitalization).

    Chemistry

    Vitamin K is a fat-soluble vitamin that is stable in air and moisture but decomposes in sunlight. It is a polycyclic aromatic ketone, based on 2-methyl-1,4-naphthoquinone, with a 3-phytyl substituent. It is found naturally in a wide variety of green plants, particularly in leaves, since it functions as an electron acceptor during photosynthesis, forming part of the electron transport chain of photosystem I.[13][14]

    The best-known function of vitamin K in animals is as a cofactor in the formation of coagulation factors II (prothrombin), VII, IX, and X by the liver. It is also required for the formation of anticoagulant factors protein C and S. It is commonly used to treat warfarin toxicity, and as an antidote for coumatetralyl.

    Vitamin K is required for bone protein formation.

    Biosynthesis

    The biosynthesis of vitamin K1 via the transformation of chorismate occurs in nine steps.

    Vitamin K1 is synthesized from chorismate, a compound produced from shikimate via the shikimate pathway. The conversion of chorismate to vitamin K1 comprises a series of nine steps:[15][16]

    1. Chorismate is isomerized to isochorismate by isochorismate synthase, or MenF (menaquinone enzyme).
    2. Addition of 2-oxoglutarate to isochorismate by PHYLLO, a multifunctional protein comprising three different enzymatic activities (MenD, H, and C).
    3. Elimination of pyruvate by PHYLLO.
    4. Aromatization to yield o-succinyl benzoate by PHYLLO.
    5. O-succinylbenzoate activation to corresponding CoA ester by MenE.
    6. Naphthoate ring formation by naphthoate synthase (MenB/NS).
    7. Thiolytic release of CoA by a thioesterase (MenH).
    8. Attachment of phytol chain to the naphthoate ring (MenA/ABC4).
    9. Methylation of the precursor at position 3 (MenG).   

    See also

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 12 "Phytonadione". The American Society of Health-System Pharmacists. Archived from the original on 29 December 2016. Retrieved 8 December 2016.
    2. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 9 August 2020. Retrieved 4 September 2020.
    3. ↑ Watson, Ronald Ross (2014). Diet and Exercise in Cystic Fibrosis. Academic Press. p. 187. ISBN 9780128005880. Archived from the original on 2016-12-30.
    4. ↑ "Phytonadione Use During Pregnancy". Drugs.com. Archived from the original on 29 December 2016. Retrieved 29 December 2016.
    5. ↑ "Office of Dietary Supplements – Vitamin K". ods.od.nih.gov. 11 February 2016. Archived from the original on 31 December 2016. Retrieved 30 December 2016.
    6. 1 2 Sneader, Walter (2005). Drug Discovery: A History. John Wiley & Sons. p. 243. ISBN 9780471899792. Archived from the original on 2016-12-30.
    7. ↑ 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.
    8. ↑ "Vitamin K1". International Drug Price Indicator Guide. Archived from the original on 10 May 2017. Retrieved 8 December 2016.
    9. ↑ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 229. ISBN 9781284057560.
    10. 1 2 "PHYTOMENADIONE = VITAMIN K1 injectable - Essential drugs". medicalguidelines.msf.org. Archived from the original on 28 August 2021. Retrieved 4 September 2020.
    11. ↑ Haroon Y, Shearer MJ, Rahim S, Gunn WG, McEnery G, Barkhan P (June 1982). "The content of phylloquinone (vitamin K1) in human milk, cows' milk and infant formula foods determined by high-performance liquid chromatography". The Journal of Nutrition. 112 (6): 1105–17. doi:10.1093/jn/112.6.1105. PMID 7086539.
    12. ↑ "Vitamin K". Archived from the original on 2013-05-22. Retrieved 2009-03-18.
    13. ↑ Itoh, Shigeru; Iwaki, Masayo (1989). "Vitamin K1 (Phylloquinone) Restores the Turnover of FeS centers of Ether-extracted Spinach PSI Particles". FEBS Letters. 243 (1): 47–52. doi:10.1016/0014-5793(89)81215-3.
    14. ↑ Palace GP, Franke JE, Warden JT (May 1987). "Is phylloquinone an obligate electron carrier in photosystem I?". FEBS Letters. 215 (1): 58–62. doi:10.1016/0014-5793(87)80113-8. PMID 3552735.
    15. ↑ Reumann S (2013). "Biosynthesis of vitamin K1 (phylloquinone) by plant peroxisomes and its integration into signaling molecule synthesis pathways". Sub-Cellular Biochemistry. Subcellular Biochemistry. Springer Netherlands. 69: 213–29. doi:10.1007/978-94-007-6889-5_12. ISBN 9789400768888. PMID 23821151.
    16. ↑ Widhalm JR, van Oostende C, Furt F, Basset GJ (April 2009). "A dedicated thioesterase of the Hotdog-fold family is required for the biosynthesis of the naphthoquinone ring of vitamin K1". Proceedings of the National Academy of Sciences of the United States of America. 106 (14): 5599–603. doi:10.1073/pnas.0900738106. PMC 2660889. PMID 19321747.
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