Griseofulvin

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Griseofulvin
Griseofulvin.svg
Griseofulvin 3D.png
Systematic (IUPAC) name
(2S,6'R)- 7-chloro- 2',4,6-trimethoxy- 6'-methyl- 3H,4'H-spiro [1-benzofuran- 2,1'-cyclohex[2]ene]- 3,4'-dione
Clinical data
Trade names Gris-peg
AHFS/Drugs.com monograph
MedlinePlus a682295
Pregnancy cat.
  • B3 (Australia), C (United States)
Legal status
  • POM (UK), ℞-only (U.S.)
Routes Oral
Pharmacokinetic data
Bioavailability Highly variable (25 to 70%)
Metabolism Hepatic demethylation and glucuronidation
Half-life 9-21 hours
Identifiers
CAS number 126-07-8 YesY
ATC code D01AA08 D01BA01
PubChem CID 441140
DrugBank DB00400
ChemSpider 389934 YesY
UNII 32HRV3E3D5 YesY
KEGG D00209 YesY
ChEBI CHEBI:27779 YesY
ChEMBL CHEMBL562 YesY
Chemical data
Formula C17H17ClO6 
Mol. mass 352.766 g/mol
 YesY (what is this?)  (verify)

Griseofulvin (marketed under the proprietary name Grifulvin V by Orthoneutrogena Labs, according to FDA orange book) is an antifungal drug that is administered orally. It is used both in animals and in humans, to treat fungal infections of the skin (commonly known as ringworm) and nails. It is produced by culture of some strains of the mold Penicillium griseofulvum, from which it was isolated in 1939.[1][2]

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[3]

Biosynthetic pathway of Griseofulvin

Biosynthetic process[edit]

The first step in the biosynthesis of Griseofulvin by Penicillium 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-adenosylmethionine (SAM) twice to grant 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 oxyidation 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 . [4] 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. [5][6]

Medical uses[edit]

Griseofulvin is used orally only for dermatophytosis. It is ineffective topically. Griseofulvin is reserved for cases with nail, hair or large body surface involvement.[7]

Side effects[edit]

Known side effects of griseofulvin include:

  • Can reduce the effectiveness of oral contraceptives as it is a cytochrome p450 enzyme inducer
  • Confusion
  • Considered unsafe for those with porphyria
  • Diarrhea
  • Dizziness
  • Fatigue
  • Headache
  • Urticaria
  • Impairment of performance of routine activities
  • Impairment of liver enzymatic activity
  • Inability to fall or stay asleep
  • Itching
  • Loss of taste sensation
  • Nausea
  • Oral thrush (yeast infection of the mouth)
  • Possibly a teratogen inducing mutations
  • Sensitivity to alcohol, with a disulfiram/antabuse-like reaction
  • Sensitivity to prolonged sun exposure
  • Skin rashes (including Steven- Johnson syndrome)
  • Swelling
  • Tingling in the hands or feet
  • Upper abdominal pain

Common brand names[edit]

  • Grifulvin V
  • Gris-PEG
  • S-Fulvin
  • Crivicin
  • Grison-250 (V.I.P Pharma)
  • Grisovin-FP (GSK)
  • Gris OD 375 (DR.REDDY'S)

Mechanism[edit]

The drug binds to tubulin, interfering with microtubule function, thus inhibiting mitosis.

It binds to keratin in keratin precursor cells and makes them resistant to fungal infections. It is only when hair or skin is replaced by the keratin-griseofulvin complex that the drug reaches its site of action. Griseofulvin will then enter the dermatophyte through energy dependent transport processes and bind to fungal microtubules. This alters the processing for mitosis and also underlying information for deposition of fungal cell walls.

References[edit]

  1. ^ Michael Ash; Irene Ash (2004). Handbook of Preservatives. Synapse Info Resources. p. 406. ISBN 978-1-890595-66-1. 
  2. ^ Goldman, Leon (6 February 1960). "Current status of Griseofulvin". Journal of the American Medical Association 172 (6): 532. doi:10.1001/jama.1960.03020060022006. 
  3. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  4. ^ Birch, Arthur (1953). "Studies in relation to biosynthesis I. Some possible routes to derivatives of orcinol and phloroglucinol". Australian Journal of Chemistry 6 (4): 360. doi:10.1071/ch9530360. 
  5. ^ Dewick, Paul M. (2009). Medicinal Natural Products: A Biosynthetic Approach (3rd ed.). UK: John Wiley & Sons Ltd. ISBN 0-471-97478-1. 
  6. ^ Harris, Constance (1976). "Biosynthesis of Griseofulvin". Journal of the American Chemical Society 98 (17): 360. 
  7. ^ Tripathi. Textbook of Pharmacology. Jaypee Brothers. pp. 761–762. ISBN 81-8448-085-7. 

External links[edit]