Evidence that formulations of the selective MAO-B inhibitor, selegiline, which bypass first-pass metabolism, also inhibit MAO-A in the human brain.

Abstract

Selegiline (L-deprenyl) is a selective, irreversible inhibitor of monoamine oxidase B (MAO-B) at the conventional dose (10 mg/day oral) that is used in the treatment of Parkinson's disease. However, controlled studies have demonstrated antidepressant activity for high doses of oral selegiline and for transdermal selegiline suggesting that when plasma levels of selegiline are elevated, brain MAO-A might also be inhibited. Zydis selegiline (Zelapar) is an orally disintegrating formulation of selegiline, which is absorbed through the buccal mucosa producing higher plasma levels of selegiline and reduced amphetamine metabolites compared with equal doses of conventional selegiline. Although there is indirect evidence that Zydis selegiline at high doses loses its selectivity for MAO-B, there is no direct evidence that it also inhibits brain MAO-A in humans. We measured brain MAO-A in 18 healthy men after a 28-day treatment with Zydis selegiline (2.5, 5.0, or 10 mg/day) and in 3 subjects receiving the selegiline transdermal system (Emsam patch, 6 mg/day) using positron emission tomography and the MAO-A radiotracer [(11)C]clorgyline. We also measured dopamine transporter (DAT) availability in three subjects from the 10 mg group. The 10 mg Zydis selegiline dose significantly inhibited MAO-A (36.9±19.7%, range 11-70%, p<0.007)) but not DAT; and while Emsam also inhibited MAO-A (33.2±28.9 (range 9-68%) the difference did not reach significance (p=0.10)) presumably because of the small sample size. Our results provide the first direct evidence of brain MAO-A inhibition in humans by formulations of selegiline, which are currently postulated but not verified to target brain MAO-A in addition to MAO-B.

• Authors: Joanna S Fowler, Jean Logan, Nora D Volkow, Elena Shumay, Fred McCall-Perez, Millard Jayne, Gene-Jack Wang, David L Alexoff, Karen Apelskog-Torres, Barbara Hubbard, Pauline Carter, Payton King, Stanley Fahn, Michelle Gilmor, Frank Telang, Colleen Shea, Youwen Xu, Lisa Muench
• Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (Neuropsychopharmacology) Vol. 40 Issue 3 Pg. 650-7 (Feb 2015) ISSN: 1740-634X [Electronic] England
• PMID: 25249059 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Carbon Radioisotopes
• Dopamine Plasma Membrane Transport Proteins
• Monoamine Oxidase Inhibitors
• Selegiline
• Monoamine Oxidase
• monoamine oxidase A, human
• Cocaine
• Clorgyline

Topics

• Administration, Cutaneous
• Administration, Oral
• Adolescent
• Adult
• Brain (drug effects, enzymology, metabolism)
• Carbon Radioisotopes (metabolism)
• Clorgyline (metabolism)
• Cocaine (metabolism)
• Dopamine Plasma Membrane Transport Proteins (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Functional Neuroimaging
• Humans
• Male
• Monoamine Oxidase (metabolism)
• Monoamine Oxidase Inhibitors (administration & dosage, pharmacology)
• Positron-Emission Tomography
• Selegiline (administration & dosage, pharmacology)
• Young Adult