Pressor response to tyramine after single 24-hour application of a selegiline transdermal system in healthy males.

Orally administered selegiline hydrochloride is a selective monoamine oxidase type B inhibitor at the recommended regimen of 10 mg/day, but it loses selectivity at higher doses. In bypassing first-pass metabolism, a 24-hour application of transdermally administered selegiline (7.8 mg/24 hr) yields fifty times greater systemic exposure than is provided by single oral doses. The current study was designed to demonstrate that, similar to the oral regimen, transdermally administered selegiline is devoid of the pressor effects associated with tyramine and classic monoamine oxidase type A inhibitors. A single-blind, staggered, parallel-group study of pressor response to tyramine during a single 24-hour application of one-quarter, one-half, or one selegiline transdermal system relative to baseline (drug-free) response to tyramine was conducted in three groups, each with five healthy male volunteers. The end point of pressor response was declared if a participant's systolic blood pressure rose by > 30 mmHg, heart rate decreased by > 25 bpm with an associated > 20-mmHg rise in systolic blood pressure, or a clinically significant change was observed in the electrocardiogram. Doses up to 600 mg were administered during the baseline phase and up to 200 mg during the active-treatment phase. Participants received escalating tyramine doses every 4 hours until the maximum or threshold dose was achieved. Doses up to 200 mg were tolerated without apparent increase in sensitivity in participants receiving one-quarter, one-half, or one selegiline transdermal system. All participants completed the trial, and no significant adverse events were reported. Monoamine oxidase type B inhibition was complete (100%) by 12 hours after initial application in all treatment groups while plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) after 24-hour application were unaffected relative to baseline. These results suggest that systemic selegiline levels may not predict the propensity for a hypertensive crisis associated with presumed nonselective doses and that the avoidance of peripheral monoamine oxidase type A inhibition in the gut via the selegiline transdermal system may provide a safe vehicle for administering selegiline at plasma levels beyond that which can be safely obtained after oral administration. These findings will need to be confirmed in a long-term dose setting.

Selegiline percutaneous absorption in various species and metabolism by human skin.

PURPOSE: A Selegiline Transdermal System (STS) is under development for indications which may not be optimally or safely treated with oral selegiline. Studies were conducted to evaluate the in vitro penetration and skin metabolism of selegiline in order to better understand the toxicological findings and the observed plasma levels of selegiline and its metabolites in animals and man. METHODS: In vitro penetration studies were conducted in four different species (male hairless mice, male and female rats, female dog and male Micropig) and compared to human skin. In another study, viable human skin was used to estimate the extent of metabolism of selegiline by human skin using Franz diffusion cells. RESULTS: Results indicated that female dog and male Micropig skin were reasonable animal models for 24 hour in vitro selegiline penetration through human skin. Penetration of selegiline through rat skin and hairless mouse skin was 2-fold and 3-fold higher than through human skin, respectively. Metabolism was negligible in human skin. Selegiline metabolites (L-methamphetamine and N-desmethylselegiline but not L-amphetamine) were detected at all time points but the extent of selegiline metabolism was negligible. The cumulative 24 hour in vitro selegiline permeation from a 1.83 mg/cm2 STS through human skin was 5.0 mg. This was similar to the in vivo permeation in humans as assessed by residual patch analysis. CONCLUSIONS: The similarity of dog and human skin permeation results support the use of the dog as a species for evaluating the toxicology of transdermally-administered selegiline. Selegiline is not metabolized cutaneously and hence the metabolic profile following STS administration is likely due to hepatic metabolism only.

Stereoselectivity and enantioselectivity of glutathione S-transferase toward stilbene oxide substrates.

Isozyme 4-4 of rat liver glutathione S-transferase catalyzes the stereoselective addition of glutathione to the oxirane carbon of R-absolute configuration of cis-stilbene oxide, 2, to give 98 +/- 2% of the (1S,2S)-1,2-diphenyl-1-(S-glutathionyl)-2-hydroxyethane product with a turnover number (kc) of 0.22 s-1. The two enantiomers of trans-stilbene oxide, 3, are somewhat poorer substrates for the enzyme. Enantioselective addition of glutathione to 3 proceeds with turnover numbers of 0.12 s-1 and 0.023 s-1 for the (R,R,)- and (S,S)-antipodes, respectively.