CYP2C19 polymorphism is not important for the in vivo metabolism of selegiline.
OBJECTIVE
To address the relevance of cytochrome P-450 (CYP) 2C19 polymorphism for the pharmacokinetics and dynamics of selegiline and its two known primary metabolites, desmethylselegiline and l-methamphetamine.


METHODS
Six extensive (mephenytoin S/R ratio < 0.3; EM) and six poor (mephenytoin S/R ratio > 0.8; PM) hydroxylators of S-mephenytoin ingested a single 10-mg oral dose of selegiline hydrochloride. Serum concentrations of selegiline, desmethylselegiline and l-methamphetamine were measured by gas chromatography--mass spectrometry for up to 48 h. In addition, the platelet monoamine oxidase type B (MAO-B) activity was measured for 14 days to describe possible differences in the pharmacodynamics of selegiline and its metabolites between EM and PM.


RESULTS
The CYP2C19 phenotype had no significant effects on the pharmacokinetic variables of selegiline. PM of S-mephenytoin had 68% higher mean AUC of desmethylselegiline (P = 0.0017) than EM, but no significant differences were observed in other pharmacokinetic parameters of desmethylselegiline. Contrary to desmethylselegiline, the serum l-methamphetamine concentrations were slightly lower in PM, but no statistically significant differences were observed in l-methamphetamine pharmacokinetics between the two CYP2C19 phenotypes. Accordingly, the magnitude of MAO-B inhibition showed no significant differences between the study groups.


CONCLUSIONS
CYP2C19 polymorphism does not seem to be crucial for the metabolism or clinical effects of selegiline.
Laine
K
K
Department of Pharmacology and Clinical Pharmacology, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland. karlai@utu.fi
Anttila
M
M
Nyman
L
L
Wahlberg
A
A
Bertilsson
L
L
D000328:Adult; D000662:Amphetamines / Q000493:pharmacokinetics; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D006899:Mixed Function Oxygenases / Q000235:genetics*; D008996:Monoamine Oxidase Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D012642:Selegiline / Q000378:metabolism* / Q000493:pharmacokinetics*
D000662:Amphetamines; D008996:Monoamine Oxidase Inhibitors; D012642:Selegiline; C017861:desmethylselegiline; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19