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

In view of conflicting data in the literature regarding the enzyme(s) respo nsible for metabolism of selegiline, a drug used in the treatment of Parkin son's disease, investigations were carried out in vitro using the human cyt ochrome P450 enzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C1 9, CYP2D6, CYP20, and CYP3A4 recombinantly expressed in yeast to elucidate the enzyme specificity in selegiline metabolism. In the yeast microsomes us ed, 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 I/h) CYP2C19 (82 I/ h), whereas CYP3A4 (27 I/h) and CYP1A2 (21 I/h) were of less importance. An tibodies against CYP2B6 inhibited metabolism of selegiline in microsomes co ntaining CYP2B6 but not in microsomes; without significant amounts of the e nzyme. In contrast to previous reports, we could not find any role for CYP2 D6 in the metabolism of selegiline. The data strongly indicate that the hig h extent of interindividual variation seen in vivo for selegiline clearance is caused by the metabolism of the compound by the highly polymorphic CYP2 B6 and CYP2C19.