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Vol. 29, Issue 11, 1480-1484, November 2001

CYP2B6 and CYP2C19 as the Major Enzymes Responsible for the Metabolism of Selegiline, a Drug Used in the Treatment of Parkinson's Disease, as Revealed from Experiments with Recombinant Enzymes

Mats Hidestrand, Mikael Oscarson, Jarmo S. Salonen, Leena Nyman, Olavi Pelkonen, Miia Turpeinen, and Magnus Ingelman-Sundberg

Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (M.H., M.O., M.I.-S.); Orion Pharma, Preclinical and Clinical R & D, Turku, Finland (J.S.S., L.N.); and Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland (O.P., M.T.)

In view of conflicting data in the literature regarding the enzyme(s) responsible for metabolism of selegiline, a drug used in the treatment of Parkinson's disease, investigations were carried out in vitro using the human cytochrome P450 enzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 recombinantly expressed in yeast to elucidate the enzyme specificity in selegiline metabolism. In the yeast microsomes used, desmethylselegiline and levomethamphetamine were formed from selegiline at significant rates. The highest contribution to the hepatic clearance of selegiline was calculated to be exerted by CYP2B6 (124 l/h) CYP2C19 (82 l/h), whereas CYP3A4 (27 l/h) and CYP1A2 (21 l/h) were of less importance. Antibodies against CYP2B6 inhibited metabolism of selegiline in microsomes containing CYP2B6 but not in microsomes without significant amounts of the enzyme. In contrast to previous reports, we could not find any role for CYP2D6 in the metabolism of selegiline. The data strongly indicate that the high extent of interindividual variation seen in vivo for selegiline clearance is caused by the metabolism of the compound by the highly polymorphic CYP2B6 and CYP2C19.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 2001 by the American Society for Pharmacology and Experimental Therapeutics.