Pharmacokinetics of terbinafine and of its five main metabolites in plasma and urine, following a single oral dose in healthy subjects

Abstract

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 Cmax 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 (approximately 25 h). As compared to the plasma concentration of total radioactivity observed after a single oral administration of the same dose of 14C-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 (approximately 57%), after administration of 14C-terbinafine. This shows in contrast to plasma, that numerous other metabolites are present in urine.

Update on terbinafine with a focus on dermatophytoses

“…58 At least seven cytochromes P450 (CYP) appear to be responsible for metabolizing terbinafi ne into more than 15 metabolites. 59 In adults, the N-demethyl and carboxybutyl metabolites constitute the largest fraction of the metabolites observed. Maximum circulating concentrations and total body exposure are comparable or in excess of those observed with the parent compound.…”

Use of Terbinafine in Mouse and Rat Models ofPneumocystis cariniiPneumonia

“…Our group uses P. carinii f. sp. carinii (6,13). In limited studies, we have found no differences in drug susceptibility among genetically different strains of rat P. carinii (8).…”

“…Using an ATP cytotoxicity assay to screen candidate anti-P. carinii drugs, our group found that terbinafine has a 50% inhibitory concentration of 3.7 g/ml against rat P. carinii at 72 h (16). Although this concentration indicates moderate activity on our rating scale (7, 28), it exceeds levels of terbinafine in serum that can be achieved in humans (1 to 2 g/ml) or rodents (2 to 2.5 g/ml) with oral administration of the drug (9,13,15,18,19,20). Here we have analyzed the efficacy of terbinafine in our mouse and rat models of pneumocystosis.…”

“…By contrast, terbinafine is active in vitro against fungi that cause systemic infections but has not been effective as therapy in animal models of these infections (8,15,21,22). Following oral administration, terbinafine binds to the stratum corneum, dermis-epidermis, sebum, hair, and nails, where it achieves concentrations higher than those in plasma (9,13,18,20). Yet, even when terbinafine reached a concentration in the lungs of about 6 g/ml after parenteral administration, the drug was ineffective in the treatment of experimental pulmonary aspergillosis (21).…”

Physiologically Based Pharmacokinetic Model for Terbinafine in Rats and Humans

“…Terbinafine is highly lipophilic and keratophilic, so it is extensively distributed throughout adipose tissue, dermis, epidermis, and nails in humans (12,19). The apparent volume of distribution in humans is relatively large and has been reported to be in the range of 780 to 2,000 liters (22,25,27,28,33). The large volume of distribution of terbinafine and its accumulation in peripheral tissue as well as the slow redistribution of the drug into blood are likely to significantly influence the half-life of terbinafine.…”