RT Journal Article
SR Electronic
T1 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
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1480
OP 1484
VO 29
IS 11
A1 Mats Hidestrand
A1 Mikael Oscarson
A1 Jarmo S. Salonen
A1 Leena Nyman
A1 Olavi Pelkonen
A1 Miia Turpeinen
A1 Magnus Ingelman-Sundberg
YR 2001
UL http://dmd.aspetjournals.org/content/29/11/1480.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics