ELIMINATION KINETICS OF TERBINAFINE FROM HUMAN PLASMA AND TISSUES FOLLOWING MULTIPLE-DOSE ADMINISTRATION, AND COMPARISON WITH 3 MAIN METABOLITES

Trough and peak concentrations as well as the elimination kinetics of the antimycotic agent terbinafine and 3 metabolites were investigated following multiple-dose administration of terbinafine 250mg daily for 4, 12 and 48 weeks. Plasma, sebum and tissues such as the stratum corn eum, dermis-epidermis, hair and nails were analysed. The elimination o f all compounds was multiphasic, being faster initially. Mean terminal elimination half-lives of the parent drug determined in plasma and ti ssues ranged from 18 to 28 days, and were in the same range as those o f the metabolites (21 to 28 days). The slowest terminal elimination of terbinafine was observed from the dermis-epidermis and from keratinic tissues like hair and nails. Trough plasma concentrations of terbinaf ine were highly consistent in all studies, indicating an accumulation (12.6- to 18.5-fold) after multiple-dose treatment. However, peak conc entrations of terbinafine accumulated only slightly (1.3-fold). In pla sma, the kinetics of the metabolites were similar with regard to their terminal elimination half-life. Like the parent drug, trough concentr ations of the N-demethylated metabolite accumulated (8- to 12.9-fold) after multiple-dose administration, but the peak concentrations did no t. In contrast, the 2 carboxy metabolites accumulated only slightly (1 .6- to 2.7-fold) under the same conditions.