title: 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.affiliation: Biological, Environmental and Climate Sciences Department, Brookhaven National Laboratory, Upton, NY, USA.
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Fowler
authors.affiliation: New York University Langone Medical Center, Department of Radiology, New York, NY, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Logan
authors.affiliation: 1] National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA [2] National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Nora D
authors.initials: ND
authors.lastname: Volkow
authors.affiliation: National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Shumay
authors.affiliation: Targeted Medical Pharma Inc, Los Angeles, CA, USA.
authors.forename: Fred
authors.initials: F
authors.lastname: McCall-Perez
authors.affiliation: National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Millard
authors.initials: M
authors.lastname: Jayne
authors.affiliation: National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Gene-Jack
authors.initials: GJ
authors.lastname: Wang
authors.affiliation: Biological, Environmental and Climate Sciences Department, Brookhaven National Laboratory, Upton, NY, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Alexoff
authors.affiliation: National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Apelskog-Torres
authors.affiliation: Biological, Environmental and Climate Sciences Department, Brookhaven National Laboratory, Upton, NY, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hubbard
authors.affiliation: Biological, Environmental and Climate Sciences Department, Brookhaven National Laboratory, Upton, NY, USA.
authors.forename: Pauline
authors.initials: P
authors.lastname: Carter
authors.affiliation: Biological, Environmental and Climate Sciences Department, Brookhaven National Laboratory, Upton, NY, USA.
authors.forename: Payton
authors.initials: P
authors.lastname: King
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Stanley
authors.initials: S
authors.lastname: Fahn
authors.affiliation: Novartis Pharmaceuticals, East Hanover, NJ, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Gilmor
authors.affiliation: National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Telang
authors.affiliation: Biological, Environmental and Climate Sciences Department, Brookhaven National Laboratory, Upton, NY, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Shea
authors.affiliation: Biological, Environmental and Climate Sciences Department, Brookhaven National Laboratory, Upton, NY, USA.
authors.forename: Youwen
authors.initials: Y
authors.lastname: Xu
authors.affiliation: National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Muench
mesh_terms: D000279:Administration, Cutaneous; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001921:Brain / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000378:metabolism; D003010:Clorgyline / Q000378:metabolism; D003042:Cocaine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D059907:Functional Neuroimaging; D006801:Humans; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D012642:Selegiline / Q000008:administration & dosage / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D002250:Carbon Radioisotopes; D050483:Dopamine Plasma Membrane Transport Proteins; D008996:Monoamine Oxidase Inhibitors; D012642:Selegiline; D008995:Monoamine Oxidase; C579458:monoamine oxidase A, human; D003042:Cocaine; D003010:Clorgyline