TOXICOKINETIC EVALUATION OF A SELEGILINE TRANSDERMAL SYSTEM IN THE DOG

The toxicology and toxicokinetics of a selegiline transdermal system ( STS) were evaluated in a 3 month dog study of daily 24 h applications of placebo 4, 8, or 12 STSs in 32 male and 32 female beagle dogs. Each STS delivered approximately 5 mg selegiline over 24 h. No drug-relate d signs of toxicity were noted in any group with respect to clinical o bservations, dermal effects, body weight, food consumption, hematology , urinalysis data, or ophthalmoscopic or electrocardiographic examinat ions. Clinical chemistry data revealed no consistent adverse effects e xcept for an increase in alanine aminotransferase in dogs receiving 8 and 12 STSs. Histological evaluation of tissues revealed the presence of pigment in the Kupffer cells of dogs treated with 8 and 12 STSs. Th ere were no pathology findings suggestive of hemolysis or cholestasis. The no-effect level (NOEL) was 4 STSs (2.9 mg kg(-1) d(-1)). There we re no degenerative or life-threatening toxic effects up to 12 STSs (8. 5 mg kg(-1) d(-1)). Gender-related differences in steady-state plasma levels were not observed. Steady-state plasma concentrations were simi lar to maximum plasma concentrations obtained in single-dose studies, suggesting that drug accumulation was not evident. Simulation of syste mic exposure following oral administration of 16.8 mg kg(-1) d(-1) fro m previous toxicology studies indicated that selegiline exposure follo wing 12 STSs is sixfold greater while N-desmethylselegiline, L-ampheta mine, and L-methamphetamine exposure is 0.5, 0.15, and 0.14 times the exposure in the oral study. The threefold difference in NOEL between o ral and transdermal studies in the dog (0.8 versus 2.9 mg kg(-1) d(-1) ) is probably related to greater L-amphetamine and L-methamphetamine e xposure following oral administration. The reduction in metabolite for mation, relative exposure of selegiline in the dog at the NOEL compare d to oral toxicology studies, and margin of safety provided, given tha t the expected clinical dose is less than the dosage of oral Eldepryl( R) (0.15 mg kg(-1) d(-1)), documents the safety of the selegiline drug substance and indicates that additional toxicologic findings with the STS may not be expected. (C) 1997 by John Wiley & Sons, Ltd.