The uptake of fluconazole in finger and toe nails

Objective: The uptake of the antimycotic agent fluconazole in finger and to e nail following various treatment schedules was investigated in order to c haracterize the pharmacokinetic basis for the systemic treatment of onychom ycosis with fluconazole. Subjects: Between 8 and 12 healthy, male and femal e Caucasian subjects were included in four separate studies. Mean age of th e subjects in the single studies ranged between 34 years (study 4, group 2; n = 4 male and 4 female) and 38 years (study 4, group 1; n = 3 male and 4 female). Methods: Fluconazole was administered orally over 4 weeks in all s tudies. The treatment schedules were 150 mg once weekly (study 1), 300 mg o nce weekly (study 2), 50 mg once daily (study 3) and 150 or 300 mg once wee kly in a parallel group study (study 4). At fixed times samples of blood, n ail cuttings and nail dust were taken, up to two months after end of treatm ent. Fluconazole was analyzed in blood plasma and in the nail samples using a highly specific and sensitive gas chromatographic procedure. Results: Hi gh concentrations of fluconazole were found in distal nail clippings with a ll three treatments. Mean maximum concentrations which occurred in the thir d or fourth week of treatment amounted to 2.1 mu g/g (150 mg/w), 5.4 mu g/g (300 mg/w) and 6.5 mu g/g (50 mg/d) in finger nails and to 9.6 mu g/g (150 mg/w), 12.3 mu g/g (300 mg/w) and 12.2 mu g/g (50 mg/d) in toe nails. The nail concentrations were 1 - 2 times (finger) and 2 - 3 times (toe) higher than the corresponding fluconazole plasma levels and were within the MIC ra nge for dermatophytes and yeasts occurring commonly in onychomycosis. The r esidence times of fluconazole in the nail plate after the end of treatment was long, with approximate halflives of 33 days in finger nail and 30 days in toe nail. In pharmacokinetic terms there was no evidence of advantages o f the daily dosage (50 mg) over the once-weekly (300 mg) dosage. Fluconazol e was found to penetrate into both finger and toe nails at a very fast rate . On the first two days of the 150 mg/w and 300 mg/w treatments, i.e. after the first dosage, fluconazole concentrations in the distal nail plates amo unted to 50 - 80% of the later observed peak levels. The initial concentrat ions in the upper dorsal plate were particularly high, with mean peak conce ntrations of 11.9 mu g/g (150 mg) and 33.7 mu g/g (300 mg) in finger nails and 5.7 mu g/g (150 mg) and 24.4 mu g/g (300 mg) in toe nails. Conclusions: Fluconazole is rapidly and highly distributed into finger and foot nail, r eaching there higher concentrations than in the plasma. The rapid initial u ptake of fluconazole in nail, which is unlike the uptake of ether antifunga l agents, suggests the existence of special routes of access to the nail fo r fluconazole, possibly based on high diffusion rates.