Isoconazole

Isoconazole is for use in the treatment of superficial fungal diseases of the skin. It displays a very broad spectrum of antimicrobial action. It is effective against dermatophytes and yeasts, yeast-like fungi (including the causative organism of pityriasis versicolor) and molds, as well against gram-positive bacteria in-vitro and against the causative organism of erythrasma.

Isoconazole penetrates rapidly into human skin and maximum drug concentrations in the horny layer and in the living skin are present 1 hour after application. High concentrations were maintained for at least 7 hours (horny layer: approx. 3500 µg/ml (corresponding to 7 mmol/l), living epidermis approx. 20 µg/ml (40 µmol/l), dermis approx. 3 µg/ml (6 µmol/l). Removal of the horny layer prior to the application increased isoconazole concentrations in the living skin approximately by a factor of 2. Drug concentrations in the horny layer and the epidermis exceeded minimum inhibitory and biocidal antimycotic concentrations (MIC) of most important pathogens (dermatophytes, molds and yeasts) several-fold and reached MIC values in the dermis.

In a further study, isoconazole could still be detected above the MIC in the stratum corneum and the hair follicles at one week after termination of a two-week application period. In some subjects, isoconazole could even be detected 14 days after the last application.

After topical application to rabbits of the antimycotic concentrations were obtained in the skin as compared to the corticosteroid-free preparation. This was interpreted as a retardation of percutaneous absorption of isoconazole as a consequence of the vasoconstrictive effect of the corticosteroid.

Isoconazole is not metabolically inactivated in the skin. Systemic load due to percutaneous absorption is low. Even after removal of the horny layer less than 1% of the applied dose has reached the systemic circulation within 4 hours exposure time.

The percutaneous absorbed portion was too low to investigate the fate of isoconazole within the human organism.Therefore 0.5 mg of 3H-labelled isoconazole was injected intravenously. Isoconazole is completely metabolised and rapidly eliminated.

2,4-Dichloromandelic acid and 2-(2,6-dichlorobenzyloxy)2(2,4-dichlorophenyl)-acetic acid were characterised as quantitatively most important metabolites. A third of the labelled substances was excreted with the urine and two thirds with the bile; 75% of the total dose was already excreted within 24 hours.

In a series of special reproduction toxicity studies, isoconazole exerted no adverse effects on any phase of the reproductive cycle. In particular, the active ingredient showed no teratogenic potential. Although no controlled clinical studies have been carried out, experience in the use of preparations containing isoconazole during pregnancy does not indicate any risk of embryotoxic effects.

In vitro and in vivo investigations for detection of gene-, chromosome- and genome mutations have not given any indications of a mutagenic potential of isoconazole.

Specific tumorigenicity studies have not been carried out with isoconazole. On the basis of the pharmacodynamic action pattern, the lack of evidence of a genotoxic potential, the structural properties and the results of chronic toxicity tests (no indication of proliferative changes), there is no suspicion of a tumorigenic potential of isoconazole.