Orally administered ketoconazole: route of delivery to the human stratum corneum

Abstract

Delivery of ketoconazole to human stratum corneum was studied. Thirteen healthy volunteers, three patients with chronic fungal disease and one patient with palmar-plantar hyperhidrosis were given 400 mg of ketoconazole daily for various lengths of time. The ketoconazole content of palmar stratum corneum, eccrine sweat, sebum, and serum was measured by high-pressure liquid chromatography (sensitivity, 0.005 to 0.010 microgram/ml). Palmar stratum corneum obtained after 7 and 14 days of daily administration contained up to 14 micrograms of ketoconazole per g. Ketoconazole was not found in sebum after 7 or 14 days of daily ingestion of the antimycotic agent. Sebum from three patients with chronic fungal infection treated for greater than 9 months contained ketoconazole (means, 4.7 micrograms/g). Thermogenic whole body eccrine sweat contained a mean of 0.059 microgram/ml on day 7 and 0.084 microgram/ml on day 14 of daily administration. Ketoconazole appeared in thermogenic whole body eccrine sweat and palmar hyperhidrotic sweat within 1 h after a single oral dose. Partition studies of ketoconazole containing eccrine sweat demonstrated a 10-fold greater concentration in the sediment phase (desquamated keratinocytes) compared with the clear supernatant phase. In vitro studies with [3H]ketoconazole-supplemented supernatant sweat revealed preferential binding to stratum corneum, hair, and nails and its partitioning to lipid-rich sebum. We conclude that eccrine sweat rapidly transports ketoconazole across the blood-skin barrier, where it may bind or partition to keratinocytes and surface lipids.

ATP binding cassette transporters in two distinct compartments of the skin contribute to transdermal absorption of a typical substrate

“…For example, ketoconazole and fluconazole are antifungal drugs employed to treat skin infection. The SC to serum concentration ratio of fluconazole after oral administration in humans was much higher than that of ketoconazole [34,35], whereas the affinity of ketoconazole for P-gp (Ki: 5.3 μM) is higher than that of fluconazole (Ki >400 μM) [36]. Therefore, if transdermal transport of ketoconazole from the epidermis to the dermis is more efficient due to its higher affinity to P-gp, the lower distribution of ketoconazole to SC compared with fluconazole can be explained by P-gp-mediated transdermal transport.…”

Pharmacokinetic Optimisation of Oral Antifungal Therapy

“…Stratum corneum concentrations average 3.1 JLg/g after ketoconazole 200 mg/day for 14 days and 4.6 JLg/g after 400mg daily for 7 days (Haneke 1987;Harris et al 1983). Ketoconazole is transported across the blood-skin barrier by sweat (Harris et al 1983).…”

“…Stratum corneum concentrations average 3.1 JLg/g after ketoconazole 200 mg/day for 14 days and 4.6 JLg/g after 400mg daily for 7 days (Haneke 1987;Harris et al 1983). Ketoconazole is transported across the blood-skin barrier by sweat (Harris et al 1983). Peak ketoconazole concentrations in skin blister fluid indicate that there is also rapid penetration of the horny layer through the epidermis (Schafer- Korting et al 1984).…”

Oral Ketoconazole in Cutaneous Fungal Infections

“…4 The first proposed route involves the incorporation of the drug into the basal layer cells of the epidermis. In approximately 3-4 weeks, these cells progress toward the surface, keratinize, cornify, and become the stratum corneum.…”