Griseofulvin is a systemic antifungal agent effective against the common dermatophytes. It is practically insoluble in water and only slightly soluble in most organic solvents. Particle sizes of griseofulvin vary from 2.7 μm (ultramicrosized) to 10 μm (microsized).
Mode of Action:
Dermatophytes concentrate griseofulvin through an energy-dependent process. Griseofulvin then disrupts the mitotic spindle by interacting with the polymerized microtubules in susceptible dermatophytes. This leads to production of multinucleate fungal cells. The inhibition of nucleic acid synthesis and the formation of hyphal cell wall material also may be involved. The result is distortion, irregular swelling, and spiral curling of the hyphae. Griseofulvin is fungistatic rather than fungicidal, except in young active cells.
Dermatophytes can be made resistant to griseofulvin in vitro.
Griseofulvin is active against Microsporum, Epidermophyton, and Trichophyton spp. It has no effect on bacteria (including Actinomyces and Nocardia spp), other fungi, or yeasts.
Plasma levels peak ~4 hr after administration PO, but absorption from the GI tract continues over a prolonged period. Absorption is highly variable and influenced by a number of factors. The rates of disaggregation and dissolution in the GI tract limit the bioavailability of griseofulvin; thus, microsized and ultramicrosized particles are usually used. High-fat meals, margarine, or propylene glycol significantly enhance GI absorption of griseofulvin and are indicated if the microsized particles are used.
Griseofulvin is deposited in keratin precursor cells within 4–8 hr of administration PO. Sweat and transdermal fluid loss appear to play an important role in griseofulvin transfer in the stratum corneum. When these cells differentiate, griseofulvin remains bound and persists in keratin, making it resistant to fungal invasion. For this reason, new growth of hair, nails, or horn is the first to become free of fungal infection. As the fungus-containing keratin is shed, it is replaced by normal skin and hair. Only a small fraction of a dose of griseofulvin remains in the body fluids or tissues.
Biotransformation and Pharmacokinetics:
Depending on the species, 10%–50% of a griseofulvin dose is excreted almost exclusively as metabolites in the urine, and the remainder in the feces for ~4–5 days after administration. The elimination half-life of griseofulvin is ~24 hr in several species. The drug can be detected in 48–72 hr at the base level of the skin, in 6–12 days in the lower quarter, and in 2–19 days in the middle section of the horny layer.
Therapeutic Indications and Dose Rates
Griseofulvin is used for dermatophyte infections in dogs, cats, calves, horses, and other domestic and exotic animal species. Most dermatophytes are sensitive, but certain species present greater therapeutic challenges than others. Several may require higher dose rates for satisfactory control.
Special Clinical Concerns
Adverse Effects and Toxicity:
Adverse effects induced by griseofulvin are rare. Nausea, vomiting, and diarrhea have been seen. Hepatotoxicity has also been reported. Animals with impaired liver function should not be given griseofulvin, because its biotransformation will be reduced and toxic levels may be reached. Idiosyncratic (Type B or Type II adverse reaction) toxicity in cats has been reported. Clinical signs are neurologic, GI, and hematologic. Griseofulvin is contraindicated in pregnant animals (especially mares and queens) because it is teratogenic.
Lipids increase GI absorption of griseofulvin. Barbiturates decrease its absorption and antifungal activity. Griseofulvin is a microsomal enzyme inducer and promotes the biotransformation of many concurrently administered drugs. The combined use of ketoconazole and griseofulvin may lead to hepatotoxicity.
Effects on Laboratory Tests:
Treatment with griseofulvin increases alkaline phosphatase, AST, and ALT. Proteinuria may be detected.