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Pressor Response to Tyramine after Single 24‐Hour Application of a Selegiline Transdermal System in Healthy Males
Author(s) -
Barrett Jeffrey S.,
Hochadel Thomas J.,
Morales Richard J.,
Rohatagi Shashank,
DeWitt Kimberly E.,
Watson Sara K.,
Darnow John,
Azzaro Albert J.,
DiSanto Anthony R.
Publication year - 1997
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1997.tb04786.x
Subject(s) - selegiline , tyramine , transdermal , blood pressure , medicine , pharmacology , anesthesia , monoamine oxidase inhibitor , regimen , heart rate , monoamine oxidase , chemistry , biochemistry , disease , parkinson's disease , enzyme
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.