Bioavailability of fluconazole in the skin after oral medication

Abstract

Summary. Fluconazole is an antimycotic drug which until now has been used mostly in the systemic therapy of yeast infections. We have now demonstrated the presence of this drug in various skin structures. After administration of 50 mg of fluconazole per day for 12 days to healthy volunteers, the following mean drug concentrations were measured: serum 1.81 μg ml‐1, sweat 4.58 μg ml‐1, dermis‐epidermis (without stratum corneum) 2.77 μg g‐1 and stratum corneum 73 μg g‐1. Thus, 4 h after the last dose the antimycotic attains a 40‐fold higher concentration in the stratum corneum than in serum. One week after ending the oral treatment, 5.8 μg g‐1 fluconazole was present in stratum corneum. After daily ingestion of 200 mg of fluconazole for 5 days there was a further increase in the mean concentration of fluconazole in stratum corneum, to 127 μg g‐1. Even 4–5 months after completing the oral treatment, fluconazole was detectable in the head hair and toenails of healthy volunteers. Fluconazole is eliminated from the stratum corneum about 2–3 times more slowly than from serum or plasma. After oral administration fluconazole evidently accumulated rapidly and intensively into the stratum corneum. The concentrations then attained or exceeded the in vitro minimal inhibitory concentrations of fluconazole for most of the dermatophytes and yeasts which are involved in cutaneous mycoses. Zusammenfassung. Fluconazol, ein bisher vor allem in der systemischen Therapie von Sproßpilzinfektionen etabliertes Antimykotikum, wird in verschiedenen Strukturen der Haut nachgewiesen. Nach oraler Einnahme von 50 mg Fluconazol einmal täglich über 12 Tage konnten an gesunden Probanden folgende mittlere Wirkstoffkonzentrationen gemessen werden: Serum 1.81 μg ml‐1. Schweiß 4.58 μg ml‐1. Dermis‐Epidermis (ohne Stratum corneum) 2.77 μg g‐1 und Stratum corneum 73 μg g‐1. Damit erreicht das Antimykotikum vier Stunden nach der letzten Einnahme im Stratum corneum eine etwa 40fach höhere Konzentration als im Serum. Eine Woche nach Ende der oralen Behandlung werden noch 5.8 μg g‐1 Fluconazol im Stratum corneum gefunden. Die tägliche Einnahme von 200 mg Fluconazol über fünt Tage zeigt zwei Stunden nach der letzten Applikation einen weiteren Anstieg der mittleren Fluconazol‐Konzentration im Stratum corneum auf 127 μg g‐1. Das Antimykotikum ist in Kopfhaaren und Zehennägeln gesunder Probanden noch vier bzw. fünf Monate nach Beendigung der oralen Therapie nachweisbar. Aus Stratum corneum wird Fluconazol zwei‐ bis dreimal langsamer als aus Serum oder Plasma eliminiert. Fluconazol akkumuliert nach oraler Einnahme schnell und intensiv im Stratum corneum. Die dabei gemessenen Konzentrationen überschreiten die in vitro ermittelten Minimalen Hemmkonzentrationen von Fluconazol gegenüber den meisten an kutanen Mykosen beteiligten Dermatophyten und Sproßpilzen.

Tissue Penetration of Antifungal Agents

“…Fluconazole concentrations within the dermis are similar to those in plasma (216,217), but concentrations in the stratum corneum are up to 40 times those in plasma (217,218) (Fig. 7).…”

“…7). The clearance of fluconazole from the stratum corneum is also significantly slower than that from the plasma and other skin layers, with concentrations that decline 2 to 3 times more slowly than the plasma concentrations (215,217,218). Interestingly, once-weekly oral dosing of 150 mg for 2 weeks results in higher fluconazole concentrations in the stratum corneum relative to those in the epidermis/dermis, sweat, and serum than those obtained by daily dosing at 50 mg for 12 days (217).…”

Study of In Vitro Drug Release and Percutaneous Absorption of Fluconazole from Topical Dosage Forms

“…Fluconazole concentration in the skin is higher than in the serum and its elimination from the SC is considerably slower than from the serum or plasma. The concentration within the skin is much higher than the minimum inhibition concentration for most dermatophytes (4,5). The prolonged skin retention of fluconazole has been attributed to its high affinity to the SC due to an interaction between fluconazole and keratin (6).…”

“…The preparations were evenly distributed on the membranes. Serial sampling was performed after 0.5, 1, 2, 4, and 6 h and fresh receptor liquid was added to receptor compartment to replace the buffer; 5 mL of receptor fluid (PBS) was taken for UV determination of fluconazole concentration at 260 nm.…”

Development and Evaluation of New Microemulsion-Based Hydrogel Formulations for Topical Delivery of Fluconazole

“…ketoconazole, itraconazole, miconazole), fluconazole is less lipophilic (log P=0.5) and has increased antifungal activity, aqueous solubility (8 mg/mL at 37°C) and higher bioavailability, due to the presence of a halogenated phenyl ring and two triazol rings (35). The FZ efficacy in the treatment of cutaneous mycosis by oral administration has been attributed to its rapid and extensive accumulation in the stratum corneum, thus the achieved concentration of FZ in the skin being higher than its concentration in the serum and also as the minimum inhibition concentration for most dermatophytes (36)(37)(38). However, it is well known that oral administration of fluconazole is often associated with adverse effects, especially gastric disorders including nausea, gastric irritation, vomiting and abdominal discomfort, which reduces the patient compliance with long-term therapy.…”