Griseofulvin

Griseofulvin
Clinical data
Trade names Gris-peg, Grifulvin V, others
AHFS/Drugs.com Monograph
MedlinePlus a682295
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration		 by mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Highly variable (25 to 70%)
Metabolism liver (demethylation and glucuronidation)
Biological half-life 9–21 hours
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.004.335
Chemical and physical data
Formula C17H17ClO6
Molar mass 352.766 g/mol
3D model (JSmol)
  (verify)

Griseofulvin is antifungal medication used to treat a number of types of dermatophytoses (ringworm).[1] This includes fungal infections of the nails and skin when antifungal creams have not worked.[2] It is taken by mouth.[1]

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.[1] Use during or in the months before pregnancy may result in harm to the baby.[1][2] Griseofulvin works by interfering with fungal mitosis.[1]

Griseofulvin was discovered in 1939 from a type of Penicillium mold.[3][4] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[5] The wholesale cost in the developing world is about 0.05 to 0.18 USD per day.[6] In the United States a course of treatment costs 100 to 200 USD.[7]

Medical uses

Griseofulvin is used orally only for dermatophytosis. It is ineffective topically. It is reserved for cases with nail, hair, or large body surface involvement.[8]

Side effects

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
  • Insomnia
  • Itching

Mechanism

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. 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 bind to fungal microtubules. This alters the processing for mitosis and also underlying information for deposition of fungal cell walls.

Biosynthetic process

It is produced industrially by fermenting the fungus Penicillium griseofulvum.[9][10][11]

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.[12] 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.[13][14]

References

  1. 1 2 3 4 5 "Griseofulvin". The American Society of Health-System Pharmacists. Retrieved 8 December 2016.
  2. 1 2 WHO Model Formulary 2008 (PDF). World Health Organization. 2009. p. 149. ISBN 9789241547659. Retrieved 8 December 2016.
  3. ↑ Block, Seymour Stanton (2001). Disinfection, Sterilization, and Preservation. Lippincott Williams & Wilkins. p. 631. ISBN 9780683307405.
  4. ↑ Michael Ash; Irene Ash (2004). Handbook of Preservatives. Synapse Info Resources. p. 406. ISBN 978-1-890595-66-1.
  5. ↑ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Retrieved 8 December 2016.
  6. ↑ "Griseofulvin". International Drug Price Indicator Guide. Retrieved 8 December 2016.
  7. ↑ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 44. ISBN 9781284057560.
  8. ↑ Tripathi. Textbook of Pharmacology. Jaypee Brothers. pp. 761–762. ISBN 81-8448-085-7.
  9. ↑ http://www.biochemj.org/bj/033/bj0330240.htm
  10. ↑ J.F. Grove, D. Ismay, J. Macmillan, T.P.C. Mulholland, M.A.T. Rogers, Chem. Ind. (London), 219 (1951).
  11. ↑ Grove, J. F.; MacMillan, J.; Mulholland, T. P. C.; Rogers, M. A. T. (1952). "762. Griseofulvin. Part IV. Structure". Journal of the Chemical Society (Resumed): 3977. doi:10.1039/JR9520003977.
  12. ↑ 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.
  13. ↑ Dewick, Paul M. (2009). Medicinal Natural Products: A Biosynthetic Approach (3rd ed.). UK: John Wiley & Sons Ltd. ISBN 0-471-97478-1.
  14. ↑ Harris, Constance (1976). "Biosynthesis of Griseofulvin". Journal of the American Chemical Society. 98 (17): 5380–5386. doi:10.1021/ja00433a053.
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