SELEGILINE PERCUTANEOUS-ABSORPTION IN VARIOUS SPECIES AND METABOLISM BY HUMAN SKIN

Purpose. A Selegiline Transdermal System (STS) is under development fo r indications which may not be optimally or safely treated with oral s elegiline. Studies were conducted to evaluate the in vitro penetration and skin metabolism of selegiline in order to better understand the t oxicological findings and the observed plasma levels of selegiline and its metabolites in animals and man. Methods. In vitro penetration stu dies were conducted in four different species (male hairless mice, mal e and female rats, female dog and male Micropig (R)) and compared to h uman skin. In another study, viable human skin was used to estimate th e extent of metabolism of selegiline by human skin using Franz diffusi on cells. Results. Results indicated that female dog and male Micropig (R) skin were reasonable animal models for 24 hour in vitro selegilin e penetration through human skin. Penetration of selegiline through ra t skin and hairless mouse skin was 2-fold and 3-fold higher than throu gh human skin, respectively. Metabolism was negligible in human skin. Selegiline metabolites (L-methamphetamine and N-desmethylselegiline bu t not L-amphetamine) were detected at all time points but the extent o f selegiline metabolism was negligible. The cumulative 24 hour in vitr o selegiline permeation from a 1.83 mg/cm(2) STS through human skin wa s 5.0 mg. This was similar to the in vivo permeation in humans as asse ssed by residual patch analysis. Conclusions. The similarity of dog an d human skin permeation results support the use of the dog as a specie s for evaluating the toxicology of transdermally-administered selegili ne. Selegiline is not metabolized cutaneously and hence the metabolic profile following STS administration is likely due to hepatic metaboli sm only.