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 to 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 PET and the MAO-A radiotracer [¹¹C]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 alsomore »
- Authors:
-
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- New York Univ., NY (United States)
- National Inst. on Drug Abuse, Bethesda, MD (United States); National Inst. on Alcohol Abuse and Alcoholism, Bethesda, MD (United States)
- National Inst. on Alcohol Abuse and Alcoholism, Bethesda, MD (United States)
- Targeted Medical Pharma Inc., Los Angeles, CA (United States)
- Columbia Univ., New York, NY (United States)
- Publication Date:
- Research Org.:
- Brookhaven National Laboratory (BNL), Upton, NY (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1183284
- Report Number(s):
- BNL-107759-2015-JA
Journal ID: ISSN 0893-133X; R&D Project: MO-085; KP1602010
- Grant/Contract Number:
- SC00112704
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Neuropsychopharmacology
- Additional Journal Information:
- Journal Volume: 40; Journal Issue: 3; Journal ID: ISSN 0893-133X
- Publisher:
- Nature
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY; brain MAO-A; MAO inhibitors; PET; selegiline; Zydis selegiline; Emsam; selegiline transdermal system; buccal mucosa absorption; positron emission tomography (PET) facility
Citation Formats
Fowler, Joanna S., Logan, Jean, Volkow, Nora D., Shumay, Elena, McCall-Perez, Fred, Gilmor, Michelle, Jayne, Millard, Wang, Gene-Jack, Alexoff, David L., Apelskog-Torres, Karen, Hubbard, Barbara, Carter, Pauline, King, Payton, Fahn, Stanley, Telang, Frank, Shea, Colleen, Xu, Youwen, and Muench, Lisa. Evidence that formulations of the selective MAO-B inhibitor, selegiline, which bypass first-pass metabolism, also inhibit MAO-A in the human brain. United States: N. p., 2015.
Web. doi:10.1038/npp.2014.214.
Fowler, Joanna S., Logan, Jean, Volkow, Nora D., Shumay, Elena, McCall-Perez, Fred, Gilmor, Michelle, Jayne, Millard, Wang, Gene-Jack, Alexoff, David L., Apelskog-Torres, Karen, Hubbard, Barbara, Carter, Pauline, King, Payton, Fahn, Stanley, Telang, Frank, Shea, Colleen, Xu, Youwen, & Muench, Lisa. Evidence that formulations of the selective MAO-B inhibitor, selegiline, which bypass first-pass metabolism, also inhibit MAO-A in the human brain. United States. https://doi.org/10.1038/npp.2014.214
Fowler, Joanna S., Logan, Jean, Volkow, Nora D., Shumay, Elena, McCall-Perez, Fred, Gilmor, Michelle, Jayne, Millard, Wang, Gene-Jack, Alexoff, David L., Apelskog-Torres, Karen, Hubbard, Barbara, Carter, Pauline, King, Payton, Fahn, Stanley, Telang, Frank, Shea, Colleen, Xu, Youwen, and Muench, Lisa. Thu .
"Evidence that formulations of the selective MAO-B inhibitor, selegiline, which bypass first-pass metabolism, also inhibit MAO-A in the human brain". United States. https://doi.org/10.1038/npp.2014.214. https://www.osti.gov/servlets/purl/1183284.
@article{osti_1183284,
title = {Evidence that formulations of the selective MAO-B inhibitor, selegiline, which bypass first-pass metabolism, also inhibit MAO-A in the human brain},
author = {Fowler, Joanna S. and Logan, Jean and Volkow, Nora D. and Shumay, Elena and McCall-Perez, Fred and Gilmor, Michelle and Jayne, Millard and Wang, Gene-Jack and Alexoff, David L. and Apelskog-Torres, Karen and Hubbard, Barbara and Carter, Pauline and King, Payton and Fahn, Stanley and Telang, Frank and Shea, Colleen and Xu, Youwen and Muench, Lisa},
abstractNote = {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 to 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 PET and the MAO-A radiotracer [¹¹C]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.},
doi = {10.1038/npp.2014.214},
journal = {Neuropsychopharmacology},
number = 3,
volume = 40,
place = {United States},
year = {Thu Oct 29 00:00:00 EDT 2015},
month = {Thu Oct 29 00:00:00 EDT 2015}
}
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