Elimination Kinetics of Terbinafine from Human Plasma and Tissues following Multiple-Dose Administration, and Comparison with 3 Main Metabolites

Summary

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 corneum, dermis-epidermis, hair and nails were analysed. The elimination of all compounds was multiphasic, being faster initially. Mean terminal elimination half-lives of the parent drug determined in plasma and tissues ranged from 18 to 28 days, and were in the same range as those of 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 terbinafine were highly consistent in all studies, indicating an accumulation (12.6- to 18.5-fold) after multiple-dose treatment. However, peak concentrations of terbinafine accumulated only slightly (1.3-fold).

In plasma, the kinetics of the metabolites were similar with regard to their terminal elimination half-life. Like the parent drug, trough concentrations of the N-demethylated metabolite accumulated (8- to 12.9-fold) after multiple-dose administration, but the peak concentrations did not. In contrast, the 2 carboxy metabolites accumulated only slightly (1.6- to 2.7-fold) under the same conditions.