Multiple-dose pharmacokinetics and distribution in tissue of terbinafine and metabolites.
The pharmacokinetics of terbinafine and its inactive metabolites SDZ 86-621 (the N-demethyl form), SDZ 280-027 (the carboxybutyl form), and SDZ 280-047 (N-demethyl- carboxybutyl form) in plasma were characterized 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. Terbinafine concentrations were also measured in sebum, hair, nail, and stratum corneum samples. Concentrations of the parent compound and metabolites were determined by validated high-performance liquid chromatography methods. Terbinafine was rapidly absorbed, with peak concentrations in plasma of 1.70 +/- 0.77 micrograms/ml occurring 1.2 +/- 0.3 h postdose. Concentrations subsequently exhibited a triphasic decline, with a terminal deposition half-life of 16.5 +/- 2.8 days. Terbinafine accumulated approximately twofold over the 4-week dosing phase. The predominant metabolite in plasma samples was SDZ 280-027; specifically, the ratios 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 metabolites SDZ 86-621, SDZ 280-027, and SDZ 280-047. Measurable concentrations 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 peripheral tissue samples for prolonged periods (weeks to months) after administration of the last dose. These pharmacokinetic properties are likely an underlying factor in the shorter treatment times and good clinical cure rates which have been reported for terbinafine in the therapy of onychomycoses and dermatomycoses.
Kovarik
J M
JM
Department of Clinical Pharmacology, Sandoz Pharma Ltd., Basel, Switzerland.
Mueller
E A
EA
Zehender
H
H
Denouël
J
J
Caplain
H
H
Millerioux
L
L
D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D006197:Hair / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008297:Male; D009281:Naphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D012629:Sebum / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D000077291:Terbinafine; D014018:Tissue Distribution
D000935:Antifungal Agents; D009281:Naphthalenes; D000077291:Terbinafine