MULTIPLE-DOSE PHARMACOKINETICS AND DISTRIBUTION IN TISSUE OF TERBINAFINE AND METABOLITES

The pharmacokinetics of terbinafine and its inactive metabolites SDZ 8 6-621 (the N-demethyl form), SDZ 280-027 (the carboxybutyl form), and SDZ 280-047 (N-demethyl-carboxybutyl form) in plasma were characterize d for 10 healthy male subjects receiving 250 mg of terbinafine orally once a day for 4 weeks and in the subsequent 8-week washout phase. Ter binafine concentrations were also measured in sebum, hair, nail, and s tratum corneum samples, Concentrations of the parent compound and meta bolites were determined by validated high-performance liquid chromatog raphy methods, Terbinafine was rapidly absorbed, with peak concentrati ons in plasma of 1.70 +/- 0.77 mu g/ml occurring 1.2 +/- 0.3 h postdos e, Concentrations subsequently exhibited a triphasic decline, with a t erminal disposition half-life of 16.5 +/- 2.8 days, Terbinafine accumu lated approximately twofold over the ii-week dosing phase, The predomi nant metabolite in plasma samples was SDZ 280-027; specifically, the r atios of metabolite area under the curve to terbinafine area under the curve following the last dose were 1.25, 1.38, and 1.08 for metabolit es SDZ 86-621, SDZ 280-027, and SDZ 280-047, respectively, Nonrenal el imination constituted the major route of clearance for terbinafine and all three metabolites, with renal elimination playing a minor additio nal role in the clearance of metabolite SDZ 280-047. Measurable concen trations of terbinafine were achieved in sebum and hair samples within the first week of administration and by week 3 in stratum corneum and nail samples. Fungicidal concentrations persisted in plasma and perip heral tissue samples for prolonged periods (weeks to months) after adm inistration of the last dose, These pharmacokinetic properties are lik ely an underlying factor in the shorter treatment times and good clini cal cure rates,which have been reported for terbinafine in the therapy of onychomycoses and dermatomycoses.