To answer the question why topically applied
lanoconazole (CAS 101530-10-3, NND-318) is so highly effective in the treatment of
dermatomycoses in both animal models and human patients, the antifungal activity of
lanoconazole in infected sites was investigated. 1. Distribution of
lanoconazole in rat skin: The distribution of
lanoconazole within the dorsal skin of rats was examined by measurement of radioactivity and microscopic autoradiography. 24 h after dermal application of 14C-lanoconazole cream formulation, 83% of the total radioactivity in the skin was recovered from the stratum corneum, and thereafter the radioactivity decreased gradually up to 96 h. Metabolite analysis showed that more than 94% of the extractable radioactivity was
lanoconazole itself after 24 and 48 h. Microautoradiograms of the skin also supported the radioactivity distribution. 2. In vitro antifungal activity in stratum corneum-containing medium: Candida albicans TIMM 2640 was incubated for 10 days at 27 degrees C in a
vitamin-supplemented yeast
carbon base medium containing 5 mg/ml of human stratum corneum and different concentrations of
lanoconazole or
bifonazole (CAS 60628-96-8, reference agent). Compared with the control culture,
lanoconazole strongly inhibited fungal growth in a concentration dependent manner at concentration above 0.1 microgram/ml, resulting in a reduction of viable cell recovery to less than 50% after 10 days. The inhibitory activity of
bifonazole was clearly weaker than that of
lanoconazole. At concentrations of 0.1-10 micrograms/ml
lanoconazole reduced keratinolytic
acid proteinase activity in the culture-supernate to 40-70% of the control value, while
bifonazole showed 50% reduction of the activity at a concentration of 10 micrograms/ml. These results indicate that
lanoconazole is mainly distributed and retained in the stratum corneum after topical application where it exerts strong antifungal activity.