INFLUENCE OF KERATIN ON THE EFFICACY OF F LUCONAZOLE

In this study we have investigated the influence of keratin on the eff icacy and pharmakokinetics of fluconazole and additional azole antifun gal agents. It is well known that the penetration and distribution of oral antifungals is strongly influenced by plasma protein binding. Esp ecially, itraconazole and ketoconazole show a high binding affinity to plasma proteins, whereas fluconazole binds only with 12%. All of thes e antifungals, however, are accumulated in the stratum corneum of the skin. These observations have stimulated interest, if structure protei ns of the skin like keratin interact with antifungals may explain of t he accumulation process. Therefore we have measured the binding kineti cs between keratin and the azoles. Keratin from sheep wool was degreas ed, purified and incubated with azole antifungals. After defined incub ation periods the azoles were extracted and assayed by thin layer chro matography following UV-detection. There was a specific binding betwee n keratin and all of the used substances. Interestingly, the binding a ffinity of fluconazole to keratin was much higher than to plasma prote ins. Thus our observations indicate that the accumulation in the strat um corneum is a consequence of the interaction between keratin and azo le derivatives.