The uptake of fluconazole in finger and toe nails
Laufen, H.; Zimmermann, T.; Yeates, R.A.; Schumacher, T.; Wildfeuer, A.
International Journal of Clinical Pharmacology and Therapeutics 37(7): 352-360
1999
ISSN/ISBN: 0946-1965 PMID: 10442510 Document Number: 498070
The uptake of fluconazole in fingernail and toenail following various treatment schedules was investigated in order to characterize the pharmacokinetic basis for the systemic treatment of onychomycosis with fluconazole. 8-12 healthy, male and female Caucasian subjects were included in 4 separate studies. Mean age of the subjects in the single studies ranged from 34 years (study 4, group 2; n=4 male and 4 female) and 38 years (study 4, group 1; n=4 male and 4 female). Fluconazole was administered orally over 4 weeks in all studies. The treatment schedules were 150 mg once weekly (study 1), 300 mg once weekly (study 2), 50 mg once daily (study 3) and 150 or 300 mg once weekly in a parallel group study (study 4). At fixed times samples of blood, nail cuttings and nail dust were taken, up to 2 months after end of treatment. Fluconazole was analysed in blood plasma and in the nail samples using a highly specific and sensitive gas chromatographic procedure. High concentrations of fluconazole were found in distal nail clippings with all 3 treatments. Mean maximum concentrations which occurred in the 3rd or 4th week of treatment amounted to 2.1 micro g/g (150 mg/w), 5.4 micro g/g (300 mg/w) and 6.5 micro g/g (50 mg/day) in fingernails and to 9.6 micro g/g (150 mg/w), 12.3 micro g/g (300 mg/w) and 12.2 micro g/g (50 mg/day) in toenails. The nail concentrations were 1- to 2-fold (fingernail) and 2- to 3-fold (toenail) higher than the corresponding fluconazole plasma levels and were within the minimum inhibitory concentration (MIC) range for dermatophytes and yeasts occurring commonly in onychomycosis. The residence times of fluconazole in the nail plate after the end of treatment was long, with approx. half-lives of 33 days in fingernail and 30 days in toenail. In pharmacokinetic terms there was no evidence of advantages of the daily dosage (50 mg) over the once-weekly (300 mg) dosage. Fluconazole penetrated into both fingernail and toenail at a very fast rate. On the first 2 days of the 150 mg/week and 300 mg/week treatments, i.e. after the first dosage, fluconazole concentrations in the distal nail plates amounted to 50-80% of the later observed peak levels. The initial concentrations in the upper dorsal plate were particularly high, with mean peak concentrations of 11.9 micro g/g (150 mg) and 33.7 micro g/g (300 mg) in fingernails and 5.7 micro g/g (150 mg) and 24.4 micro g/g (300 mg) in toenails. It is concluded that fluconazole is rapidly and highly distributed into fingernail and toenail, reaching higher concentrations there than in the plasma.