PHARMACOKINETICS OF TERBINAFINE AND OF ITS 5 MAIN METABOLITES IN PLASMA AND URINE, FOLLOWING A SINGLE ORAL DOSE IN HEALTHY-SUBJECTS

The plasma pharmacokinetics, and the urinary excretion, of terbinafine and its five main metabolites have been investigated after a single oral dose administration of 125 mg to 16 healthy subjects. In plasma, the highest concentrations are observed for the two carboxybutyl metabolites, with a predominance for the carboxybutylterbinafine. For this metabolite, as compared to terbinafine, the C-max and AUC are 2.4 and 13 times higher respectively. The demethylterbinafine presents a plasma profile close to that of terbinafine. The two hydroxy metabolites are only found as glucuronide and are of minor importance. The apparent terminal half-lives of terbinafine, demethylterbinafine, and the two carboxy metabolites appear to be similar (similar to 25 h). As compared to the plasma concentration of total radioactivity observed after a single oral administration of the same dose of C-14-terbinafine, the parent drug and these five metabolites, account for more than 80% of the total radioactivity in plasma over the 0-48 h interval following administration. In urine, the major metabolite is demethylcarboxybutylterbinafine, which amounted to about 10% of the administered dose. Terbinafine and demethylterbinafine are only excreted as trace amounts in urine. Carboxybutylterbinafine and the two hydroxy metabolites are excreted in the range of 0.5-2% either as glucuronides or free. Urinary excretion over the 0-48 h interval of terbinafine and of the five metabolites amounted to about 14% of the administered dose. This is far below the level of total radioactivity measured in urine over the same interval (similar to 57%), after administration of C-14-terbinafine. This shows in contrast to plasma, that numerous other metabolites are present in urine.