Griseofulvin
{{Short description|Antifungal medication used for dermatophytoses}}
{{Use dmy dates|date=March 2024}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
| Watchedfields = changed
| verifiedrevid = 459852842
| IUPAC_name = (2S,6
| image = Griseofulvin.svg
| image_class = skin-invert-image
| width =
| alt =
| image2 = Griseofulvin 3D.png
| width2 =
| alt2 =
| tradename = Gris-peg, Grifulvin V, others
| Drugs.com = {{drugs.com|monograph|griseofulvin}}
| MedlinePlus = a682295
| pregnancy_AU = D
| routes_of_administration = By mouth
| ATC_prefix = D01
| ATC_suffix = AA08
| ATC_supplemental = {{ATC|D01|BA01}}
| legal_AU = S4
| legal_UK = POM
| legal_US = Rx-only
| bioavailability = Highly variable (25 to 70%)
| protein_bound =
| metabolism = Liver (demethylation and glucuronidation)
| elimination_half-life = 9–21 hours
| excretion =
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 126-07-8
| PubChem = 441140
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00400
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 389934
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 32HRV3E3D5
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00209
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 27779
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 562
| synonyms =
| C=17 | H=17 | Cl=1 | O=6
| SMILES = O=C2c3c(O[C@@]21C(/OC)=C\C(=O)C[C@H]1C)c(Cl)c(OC)cc3OC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C17H17ClO6/c1-8-5-9(19)6-12(23-4)17(8)16(20)13-10(21-2)7-11(22-3)14(18)15(13)24-17/h6-8H,5H2,1-4H3/t8-,17+/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = DDUHZTYCFQRHIY-RBHXEPJQSA-N
}}
Griseofulvin is an antifungal medication used to treat a number of types of dermatophytoses (ringworm). This includes fungal infections of the nails and scalp, as well as the skin when antifungal creams have not worked. It is taken by mouth.{{cite web|title=Griseofulvin|url=https://www.drugs.com/monograph/griseofulvin.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161220231300/https://www.drugs.com/monograph/griseofulvin.html|archive-date=20 December 2016}}
Common side effects include allergic reactions, nausea, diarrhea, headache, trouble sleeping, and feeling tired. It is not recommended in people with liver failure or porphyria. Use during or in the months before pregnancy may result in harm to the baby.{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization | hdl-access=free | page=149 }} Griseofulvin works by interfering with fungal mitosis.
Griseofulvin was discovered in 1939 from the soil fungus Penicillium griseofulvum.{{cite book| vauthors = Block SS |title=Disinfection, Sterilization, and Preservation|date=2001|publisher=Lippincott Williams & Wilkins|isbn=9780683307405|page=631|url=https://books.google.com/books?id=3f-kPJ17_TYC&pg=PA631|language=en|url-status=live|archive-url=https://web.archive.org/web/20161220092415/https://books.google.ca/books?id=3f-kPJ17_TYC&pg=PA631|archive-date=20 December 2016}}{{cite book| vauthors = Ash M, Ash I |title=Handbook of Preservatives|url=https://books.google.com/books?id=XZ2QB7bu5LwC&pg=PA406|year=2004|publisher=Synapse Info Resources|isbn=978-1-890595-66-1|pages=406|url-status=live|archive-url=https://web.archive.org/web/20131231115328/http://books.google.com/books?id=XZ2QB7bu5LwC&pg=PA406|archive-date=31 December 2013}}{{cite journal | vauthors = Beekman AM, Barrow RA | title = Fungal metabolites as pharmaceuticals | journal = Australian Journal of Chemistry | volume = 67 | issue =6| pages = 827–843| year = 2014| doi=10.1071/ch13639}} It is on the World Health Organization's List of Essential Medicines.{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}
Medical uses
Griseofulvin is used orally only for dermatophytosis. It is ineffective topically. It is reserved for cases in which topical treatment with creams is ineffective.{{Cite book| vauthors = Mutschler E, Schäfer-Korting M |title=Arzneimittelwirkungen|language=German|location=Stuttgart|publisher=Wissenschaftliche Verlagsgesellschaft|year=2001|edition=8|page=838|isbn=3-8047-1763-2}}
Terbinafine given for 2 to 4 weeks is at least as effective as griseofulvin given for 6 to 8 weeks for treatment of Trichophyton scalp infections. However, griseofulvin is more effective than terbinafine for treatment of Microsporum scalp infections.{{cite journal | vauthors = Fleece D, Gaughan JP, Aronoff SC | title = Griseofulvin versus terbinafine in the treatment of tinea capitis: a meta-analysis of randomized, clinical trials | journal = Pediatrics | volume = 114 | issue = 5 | pages = 1312–1315 | date = November 2004 | pmid = 15520113 | doi = 10.1542/peds.2004-0428 | s2cid = 34976866 }}{{cite journal | vauthors = Chen X, Jiang X, Yang M, González U, Lin X, Hua X, Xue S, Zhang M, Bennett C | title = Systemic antifungal therapy for tinea capitis in children | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | issue = 5 | pages = CD004685 | date = May 2016 | pmid = 27169520 | pmc = 8691867 | doi = 10.1002/14651858.CD004685.pub3 }}
Pharmacology
=Pharmacodynamics=
The drug binds to tubulin, interfering with microtubule function, thus inhibiting mitosis.{{cite journal | vauthors = Aris P, Wei Y, Mohamadzadeh M, Xia X | title = Griseofulvin: An Updated Overview of Old and Current Knowledge | journal = Molecules | volume = 27 | issue = 20 | pages = 7034 | date = October 2022 | pmid = 36296627 | pmc = 9610072 | doi = 10.3390/molecules27207034 | doi-access = free }} It binds to keratin in keratin precursor cells and makes them resistant to fungal infections. The drug reaches its site of action only when hair or skin is replaced by the keratin-griseofulvin complex. Griseofulvin then enters the dermatophyte through energy-dependent transport processes and binds to fungal microtubules. This alters the processing for mitosis and also underlying information for deposition of fungal cell walls.{{cn|date=December 2022}}
Biosynthesis
It is produced industrially by fermenting the fungus Penicillium griseofulvum.{{cite journal | vauthors = Oxford AE, Raistrick H, Simonart P | title = Studies in the biochemistry of micro-organisms: Griseofulvin, C(17)H(17)O(6)Cl, a metabolic product of Penicillium griseo-fulvum Dierckx | journal = The Biochemical Journal | volume = 33 | issue = 2 | pages = 240–248 | date = February 1939 | pmid = 16746904 | pmc = 1264363 | doi = 10.1042/bj0330240 }}{{cite journal | vauthors = Grove JF, Ismay D, Macmillan J, Mulholland TP, Rogers MA | title = The structure of griseofulvin. | journal = Chemistry and Industry | location = London | volume = 11 | pages = 219–220 | date = 1951 }}{{Cite journal | doi = 10.1039/JR9520003977 | title = 762. Griseofulvin. Part IV. Structure| journal = Journal of the Chemical Society (Resumed)| pages = 3977| year = 1952| vauthors = Grove JF, MacMillan J, Mulholland TP, Rogers MA }}
The first step in the biosynthesis of griseofulvin by P. griseofulvin is the synthesis of the 14-carbon poly-β-keto chain by a type I iterative polyketide synthase (PKS) via iterative addition of 6 malonyl-CoA to an acyl-CoA starter unit. The 14-carbon poly-β-keto chain undergoes cyclization/aromatization, using cyclase/aromatase, respectively, through a Claisen and aldol condensation to form the benzophenone intermediate. The benzophenone intermediate is then methylated via S-adenosyl methionine (SAM) twice to yield griseophenone C. The griseophenone C is then halogenated at the activated site ortho to the phenol group on the left aromatic ring to form griseophenone B. The halogenated species then undergoes a single phenolic oxidation in both rings forming the two oxygen diradical species. The right oxygen radical shifts alpha to the carbonyl via resonance allowing for a stereospecific radical coupling by the oxygen radical on the left ring forming a tetrahydrofuranone species.{{cite journal| vauthors = Birch A |title=Studies in relation to biosynthesis I. Some possible routes to derivatives of orcinol and phloroglucinol|journal=Australian Journal of Chemistry|date= 1953|volume=6|issue=4|pages=360|doi=10.1071/ch9530360}} The newly formed grisan skeleton with a spiro center is then O-methylated by SAM to generate dehydrogriseofulvin. Ultimately, a stereoselective reduction of the olefin on dehydrogriseofulvin by NADPH affords griseofulvin.{{cite book| vauthors = Dewick PM |title=Medicinal Natural Products: A Biosynthetic Approach (3rd ed.)|year=2009|publisher=John Wiley & Sons Ltd|location=UK|isbn=978-0-471-97478-9}}{{cite journal | vauthors = Harris CM, Roberson JS, Harris TM | title = Biosynthesis of griseofulvin | journal = Journal of the American Chemical Society | volume = 98 | issue = 17 | pages = 5380–5386 | date = August 1976 | pmid = 956563 | doi = 10.1021/ja00433a053 | bibcode = 1976JAChS..98.5380H }}
Toxicology
=Mice=
Griseofulvin is found to alter the bile metabolism of mice by Yokoo et al. 1979. The same team went on to find a similar effect on mice by a chemically unrelated substance, 3,5-diethoxycarbonyl-1,4-dihydrocollidine, in Yokoo et al. 1982 and Tsunoo et al. 1987.{{cite journal | vauthors = Knasmüller S, Parzefall W, Helma C, Kassie F, Ecker S, Schulte-Hermann R | title = Toxic effects of griseofulvin: disease models, mechanisms, and risk assessment | journal = Critical Reviews in Toxicology | volume = 27 | issue = 5 | pages = 495–537 | date = September 1997 | pmid = 9347226 | doi = 10.3109/10408449709078444 | publisher = Taylor & Francis }}
References
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Category:World Health Organization essential medicines