Selegiline metabolism and cytochrome P450 enzymes: in vitro study in human liver microsomes

Pharmacol Toxicol. 2000 May;86(5):215-21. doi: 10.1034/j.1600-0773.2000.d01-38.x.


Although being a drug therapeutically used for a long time, the enzymatic metabolism of selegiline has not been adequately studied. In the current work we have studied the cytochrome P450 (CYP)-catalyzed oxidative metabolism of selegiline to desmethylselegiline and 1-methamphetamine and the effects of selegiline, desmethylselegiline and 1-methamphetamine on hepatic CYP enzymes in human liver microsomes in vitro. The apparent Km values for desmethylselegiline and 1-methamphetamine formation were on an average 149 microM and 293 microM, and the apparent Vmax values, 243 pmol/min./mg and 1351 pmol/min./mg, respectively. Furafylline and ketoconazole, the known reference inhibitors for CYP1A2 and CYP3A4, respectively, inhibited the formation of desmethylselegiline with Ki value of 1.7 microM and 15 microM. Ketoconazole inhibited also the formation of 1-methamphetamine with Ki of 18 microM. Fluvoxamine, an inhibitor of CYP1A2, CYP2C19 and CYP3A4, inhibited the formation of desmethylselegiline and 1-methamphetamine with Ki values of 9 and 25 microM, respectively. On the basis of these results we suggest that CYP1A2 and CYP3A4 contribute to the formation of desmethylselegiline and that CYP3A4 participates in the formation of 1-methamphetamine. In studies with CYP-specific model activities, both selegiline and desmethylselegiline inhibited the CYP2C19-mediated S-mephenytoin 4'-hydroxylation with average IC50 values of 21 microM and 26 microM, respectively. The Ki for selegiline was determined to be around 7 microM. Selegiline inhibited CYP1A2-mediated ethoxyresorufin O-deethylation with a Ki value of 76 microM. Inhibitory potencies of selegiline, desmethylselegiline and 1-methamphetamine towards other CYP-model activities were much lower. On this basis, selegiline and desmethylselegiline were shown to have a relatively high affinity for CYP2C19, but no evidence about selegiline metabolism by CYP2C19 was obtained.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphetamines / pharmacology
  • Aryl Hydrocarbon Hydroxylases*
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / drug effects
  • Cytochrome P-450 Enzyme System / metabolism*
  • Fluvoxamine / pharmacology
  • Humans
  • Ketoconazole / pharmacology
  • Methamphetamine / metabolism
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology*
  • Mixed Function Oxygenases / drug effects
  • Mixed Function Oxygenases / metabolism
  • Monoamine Oxidase Inhibitors / metabolism*
  • Monoamine Oxidase Inhibitors / pharmacology
  • Selegiline / metabolism*
  • Selegiline / pharmacology
  • Theophylline / analogs & derivatives*
  • Theophylline / pharmacology


  • Amphetamines
  • Cytochrome P-450 Enzyme Inhibitors
  • Monoamine Oxidase Inhibitors
  • Selegiline
  • Methamphetamine
  • desmethylselegiline
  • Cytochrome P-450 Enzyme System
  • Theophylline
  • furafylline
  • Mixed Function Oxygenases
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19
  • Fluvoxamine
  • Ketoconazole