Chemical formula: C₁₇H₁₇ClO₆ Molecular mass: 352.766 g/mol PubChem compound: 441140
Griseofulvin is an antifungal antibiotic that is active in vivo against common dermatophytes. The antifungal effect is manifested by binding to tubulin, at distinct binding sites, thus interferring with the microtubule function and causing inhibition of mitosis, and arresting cell division. The inhibition of fungal mitosis leads to the production of multinucleate cells of characteristic morphology.
Griseofulvin when applied topically, penetrates the skin in the tissues of which it remains active against dermatophyte infections even after subsequent evaporation of the solvent system.
On entering the systemic circulation, griseofulvin binds to keratin in keratin precursor cells, thereby making them resistant to fungal infections. The drug only reaches the site of action when hair or skin is replaced by the keratin-griseofulvin complex.
Griseofulvin then enters the dermatophyte through energy dependent transport processes and binds to the fungal microtubules, interferring with, and inhibiting mitosis, and the deposition of fungal cell walls.
Griseofulvin has antifungal activity against the following dermatophytes, although there is species and strain variability in susceptibility.
Trichophyton rubrum, T. tonsurans, T. mentagrophytes, T. interdigitalis, T. verrucosum, T. megnini, T. gallinae, T. Crateriform, T. sulphureum and T. schoenleinii.
Microsporum audouinii, M. Canis, M. gypseum.
Epidermophyton floccosum.
Griseofulvin has no activity against dermatophyte fungi of other genera, non-dermatophyte fungi, yeasts, gram positive bacteria, or gram negative bacteria. If any of these are cofactors in the pathology of infection, suitable additional therapy will be required for their eradication.
The absorption of griseofulvin from the gastrointestinal tract is varaible and incomplete. On average, less than 50% of the oral dose is absorbed, but administration after a fatty meal, and a reduction in particle size will increase the rate and extent of the absorption.
Following oral administration there is a phase of rapid absorption, and thereafter a phase of slower prolonged absorption.
Peak plasma levels, 0.5 μg/ml-1.5 μg/ml after a 500 mg dose, and 1.5 μg/ml-3.0 μg/ml after a 1000 mg dose, are reached in 2-4 hours, and are maintained for some 10-20 hours.
Griseofulvin exhibits linear pharmacokinetics.
Studies in humans have demonstrated no significant absorption after cutaneous use.
The volume of distribution is about 0.7 L/Kg, and griseofulvin is ca 80% bound to plasma proteins, predominantly serum albumin.
Griseofulvin crosses the placenta, and may be excreted in breast milk. There is selective deposition of griseofulvin in newly formed keratin of hair, skin, and nails, which gradually moves to the surface of these appendages.
Griseofulvin undergoes metabolism to inactive metabolites, principally 6-desmethylgriseofulvin, or its glucuronide conjugate.
The terminal plasma half life ranges from 9.5-21 hours, with considerable intersubject variability. The majority of the dose, as 6-desmethylgriseofulvin or the glucuronide conjugate, and other metabolites is excreted in the urine, with less than 1% administered dose beinge excreted as unchanged griseofulvin. The remainder of the dose, principally as metabolites, is excreted in bile and faeces.
Renal insufficiency does not lead to accumulation.
Griseofulvin can induce aneuploidy and meiotic delay in mouse oocytes following oral administration of high doses, i.e. 250mg/kg or greater. In addition, griseofulvin caused increases in numerical and structural chromosome aberrations in mouse spermatocytes at doses of 500mg/kg and above. Aneuploidy was observed at doses of 1500mg/kg.
Griseofulvin administered to rats and mice during pregnancy has been associated with foetotoxicity and foetal malformations. Long-term administration of high doses of griseofulvin with food has been reported to induce hepatomas in mice and thyroid tumours in rats but not hamsters. The effects in mice may be due to a species specific effect on porphyrin metabolism.
Twenty-eight day studies of the effects of griseofulvin, benzyl alcohol, acetone and isopropyl alcohol on the skin of rabbits showed few signs of dermal irritation.
Systemic absorption after topical administration of griseofulvin to shaved rats is poor, being approximately 20% in 24 hours. The data suggest a reduced systemic absorption in man by the topical route and a much more favourable distribution between the dermis and the skin.
In human volunteer studies, serum concentrations after topical administration of high doses are too small to be measured.
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