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 metaboli sm, a 24-hour application of transdermally administered selegiline (7. 8 mg/24 hr) yields fifty times greater systemic exposure than is provi ded by single oral doses. The current study was designed to demonstrat e that, similar to the oral regimen, transdermally administered selegi line is devoid of the pressor effects associated with tyramine and cla ssic monoamine oxidase type A inhibitors. A single-blind, staggered, p arallel-group study of pressor response to tyramine during a single 24 -hour application of one-quarter, one-half, or one selegiline transder mal system relative to baseline (drug-free) response to tyramine was c onducted 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 clinical ly 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 t yramine doses every 4 hours until the maximum or threshold dose was ac hieved. Doses up to 200 mg were tolerated without apparent increase in sensitivity in participants receiving one-quarter, one-half, or one s elegiline transdermal system. All participants completed the trial, an d 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-hydroxyphe nylglycol (MHPG) after 24-hour application were unaffected relative to baseline. These results suggest that systemic selegiline levels may n ot predict the propensity for a hypertensive crisis associated with pr esumed nonselective doses and that the avoidance of peripheral monoami ne oxidase type A inhibition in the gut via the selegiline transdermal system may provide a safe vehicle for administering selegiline at pla sma levels beyond that which can be safely obtained after oral adminis tration. These findings will need to be confirmed in a long-term dose setting.