Nail penetration of the antifungal agent oxiconazole after repeated topical application in healthy volunteers, and the effect of acetylcysteine

Abstract Poor response of fungal nail infections to topical treatment with antimycotics is probably related to poor drug penetration into the infected nail. The aim of the present study was to evaluate the in vivo nail penetration of the antimycotic oxiconazole from a 1% w/v lotion, and to evaluate the potential penetration enhancing properties of co-delivered acetylcysteine. Six healthy volunteers were treated with 1% w/v oxiconazole lotions with or without acetylcysteine (15% w/v), according to a left–right study design. Treatment was performed twice daily for 6 weeks. Nail clippings were collected every 2 weeks over an 8-week period, until 2 weeks after the treatment stopped. Oxiconazole levels at various depths in sectioned nail clippings were measured by gas chromatographic analysis of ethanolic nail extracts. Topical treatment with oxiconazole nitrate without acetylcysteine resulted in maximum drug levels in the upper 0–50-μm layers varying between 120 and 1420 ng mg−1; levels decreased downwards. Total uptake into the nail was less than 0.2% of the topical dose, indicating a substantial barrier function of the nail. Co-delivery with acetylcysteine statistically significantly prolonged the mean residence time of oxiconazole in the upper 51–100-μm ring finger nail layers from 3.7–4.9 weeks to 4.1–6.4 weeks, implying increased retention of the drug in the nail. Mean (±S.D.) peak drug levels increased from 790±420 ng mg−1 to 1570±820 ng ml−1 in the upper 0–50-μm layer, which suggested a variably enhancing effect of acetylcysteine on the extent of oxiconazole nail penetration in the upper nail layers. The effect of acetylcysteine was speculated to be related to increased binding of oxiconazole to nail constituents.