griseofulvin

griseofulvin
IUPAC name	(2S,6'R)-7-chloro-2',4,6-trimethoxy-6'-methylspiro[benzofuran-2(3H),1'-cyclohex[2]ene]-3,4'-dione
Width	200
Tradename	Gris-PEG, Grifulvin V, others
Drugs.com	monograph, griseofulvin
Pregnancy AU	B2
Routes of administration	By mouth
Bioavailability	Variable, absorption enhanced with fatty meal
Protein bound	High
Metabolism	Hepatic (CYP450 system)
Elimination half-life	9–24 hours
Excretion	Urine, feces, sweat
CAS number	126-07-8
PubChem	441140
DrugBank	DB00400
ChemSpiderID	389962
UNII	32HRV3E3D5
ChEBI	25433
ChEMBL	70
ATC prefix	D01
ATC suffix	AA08
ATC supplemental	J02AA01

griseofulvin is an antifungal medication used primarily to treat dermatophyte infections of the skin, hair, and nails. It is derived from the mold Penicillium griseofulvum and functions by disrupting fungal cell division. The drug is administered orally and has been a cornerstone in medical mycology since its clinical introduction in the late 1950s.

Medical uses

Griseofulvin is indicated for the treatment of tinea capitis, tinea corporis, tinea pedis, tinea unguium, and tinea barbae caused by susceptible species of the genera Trichophyton, Microsporum, and Epidermophyton. Its use has been largely supplanted by newer agents like terbinafine and itraconazole for many indications, but it remains a first-line therapy for tinea capitis in many pediatric populations due to its established safety profile. The drug is not effective against Candida albicans or bacterial infections, limiting its scope to specific dermatophyte infections.

Mechanism of action

The antifungal activity of griseofulvin stems from its ability to bind to tubulin, a protein essential for microtubule formation. This binding disrupts the mitotic spindle apparatus during metaphase, arresting fungal cell division. The drug exhibits a high affinity for fungal tubulin over mammalian tubulin, providing selective toxicity. This disruption of mitosis leads to the production of multinucleated, aberrant fungal cells that are unable to proliferate, ultimately clearing the infection.

Pharmacokinetics

Oral absorption of griseofulvin is variable and significantly enhanced when taken with a high-fat meal, as it is a lipophilic compound. It is extensively metabolized in the liver by the cytochrome P450 system, primarily by the CYP3A4 isoenzyme. The drug is highly protein-bound and concentrates in the keratin precursor cells of the skin, hair, and nails, where it is incorporated into new growth. Elimination occurs via urine, feces, and sweat, with a plasma half-life ranging from 9 to 24 hours.

Adverse effects

Common adverse effects include headache, nausea, and skin rash. More serious but rare reactions can involve hepatotoxicity, necessitating monitoring of liver function tests. The drug is known to cause photosensitivity and can precipitate or exacerbate systemic lupus erythematosus. Due to its structural similarity to colchicine, it may have teratogenic effects and is contraindicated in pregnancy. Griseofulvin also induces hepatic CYP450 enzymes, leading to numerous drug interactions, including reduced efficacy of warfarin and oral contraceptives.

History

Griseofulvin was first isolated in 1939 from Penicillium griseofulvum by researchers at the University of Oxford, including Harold Raistrick. Its antifungal properties were not recognized until the 1940s during investigations by the British Ministry of Agriculture. The pivotal discovery of its systemic activity against dermatophytes was made in 1958 by Gentles J.C., working in Glasgow. This led to its rapid clinical adoption, marking a revolution in the treatment of ringworm and making it one of the first orally effective antifungal agents.

Production

The commercial production of griseofulvin is achieved through the fermentation of certain Penicillium species, notably Penicillium patulum and Penicillium griseofulvum, in large-scale bioreactors. The process involves submerged culture fermentation, followed by extraction and purification of the crystalline compound. Significant manufacturing contributions have come from pharmaceutical companies like Schering-Plough and GlaxoSmithKline. Advances in industrial microbiology and strain improvement programs have optimized yields for this naturally derived secondary metabolite.

Category:Antifungal drugs Category:World Health Organization essential medicines Category:Benzofurans